pathogens
Review
Small Molecule Compounds, A Novel Strategy against
Streptococcus mutans
Sirui Yang 1,2 , Jin Zhang 1,2 , Ran Yang 1,3, * and Xin Xu 1,2, *






Citation: Yang, S.; Zhang, J.; Yang, R.;
Xu, X. Small Molecule Compounds, A
Novel Strategy against Streptococcus
mutans. Pathogens 2021, 10, 1540.
https://doi.org/10.3390/
pathogens10121540
Academic Editors: Angela H. Nobbs
and Lawrence S. Young
Received: 5 October 2021
Accepted: 22 November 2021
Published: 25 November 2021
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iations.
Copyright: © 2021 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
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Pathogens 2021, 10, 1540. https://doi.org/10.3390/pathogens10121540
1 State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases,
Chengdu 610041, China; 2019224035135@stu.scu.edu.cn (S.Y.); zhangjin0831@stu.scu.edu.cn (J.Z.)
2 Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University,
Chengdu 610041, China
3 Department of Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University,
Chengdu 610041, China
* Correspondence: yangran@scu.edu.cn (R.Y.); xin.xu@scu.edu.cn (X.X.)
Abstract: Dental caries, as a common oral infectious disease, is a worldwide public health issue. Oral
biofilms are the main cause of dental caries. Streptococcus mutans (S. mutans) is well recognized as the
major causative factor of dental caries within oral biofilms. In addition to mechanical removal such
as tooth brushing and flossing, the topical application of antimicrobial agents is necessarily adjuvant
to the control of caries particularly for high-risk populations. The mainstay antimicrobial agents for
caries such as chlorhexidine have limitations including taste confusions, mucosal soreness, tooth
discoloration, and disruption of an oral microbial equilibrium. Antimicrobial small molecules are
promising in the control of S. mutans due to good antimicrobial activity, good selectivity, and low
toxicity. In this paper, we discussed the application of antimicrobial small molecules to the control of
S. mutans, with a particular focus on the identification and development of active compounds and
their modes of action against the growth and virulence of S. mutans.
Keywords: small molecules; Streptococcus mutans; drug repurposing; sortase A; glucosyltransferases (Gtfs)
1. Introduction
Dental caries is a chronic infectious disease across all ages of human beings [1], which
seriously endangers human oral and general health and affects the quality of life [2]. Under
normal conditions, the oral flora maintains a symbiotic relationship with the host [3].
However, under cariogenic conditions, such as frequent sugar intake, cariogenic bacteria
compete with oral commensals and cause microbial dysbiosis. The dysbiosis of oral
biofilm metabolizes carbohydrates and produces excessive acid, leading to pH declination
and consequently tooth demineralization and tooth decay [4–6]. Among oral biofilms,
Streptococcus mutans (S. mutans) is well recognized as the major cariogenic species due
to its acidogenicity and aciduricity. Besides, S. mutans synthesizes exopolysaccharides
(EPSs), which mediate the adhesion between cells and the tooth surface and contribute to
the formation of oral biofilms and the development of dental caries [7,8]. Compared to
planktonic cells, microbial biofilms show higher tolerance to acid and higher resistance to
antimicrobial drugs [9]. Therefore, the control of S. mutans, particularly in its biofilm forms,
is in great urgency.
Mechanical plaque removal and the application of chemotherapeutics are commonly
used for the control of dental caries. Daily mechanical plaque control including tooth
brushing and flossing is commonly used at all age groups for the prevention of dental
caries. However, in the high-risk group for caries, the topical application of antimicrobials
is necessary [10]. Broad-spectrum antimicrobials such as chlorhexidine digluconate (CHX)
are widely used to control cariogenic pathogens [11]. However, CHX has limitations such
as taste confusions, mucosal soreness, tooth discoloration, and drug resistance [12,13].
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Therefore, new strategies or agents to control caries are needed. Small molecules are
compounds with a molecular weight of less than 1000 Da [14]. Recently, small molecules
have become promising alternatives for the control of oral biofilms due to good cell
permeability, good stability, low cost, and low toxicity [15,16]. Various antimicrobial
small molecules from natural products and synthetic compounds have been identified
and developed. In this review, we aim to discuss antimicrobial small molecules against
S. mutans based on the way they are developed, with a particular focus on their modes of
action and mechanisms against the growth and virulence of S. mutans.

2. Drug Repurposing
Drug repurposing, also known as drug repositioning, is a commonly used drug
development approach. Compared to new drug development, drug repurposing has many
advantages including lower drug development cost, lower toxicity, and faster benchtop-to-
clinic transition [17]. Besides, due to the long-term use of broad-spectrum antimicrobial
agents, drug resistance is becoming increasingly prevalent in S. mutans [18]. Repositioning
existing drugs as antibiotics is necessary for saving manpower and material sources. Small-
molecule compounds exhibiting antimicrobial activity against other microorganisms have
been widely screened for new uses against S. mutans.
Screening FDA-approved drugs is an effective way to identify old drugs with new
therapeutic effects against S. mutans. Saputo et al. screened 853 FDA-approved drugs
and identified 126 candidates that exhibit antimicrobial activity against planktonic growth
of S. mutans, among which 24 drugs inhibit biofilm formation, 6 drugs kill pre-existing
biofilms, and 84 drugs exhibit both bacteriostatic and bactericidal effects against S. mutans
biofilms. The 126 candidates were further classified into 6 categories, including antibacteri-
als, ion channel effectors, antineoplastic drugs, antifungals, stains and disulfiram, many of
which are small molecules such as biapenem, cefdinir, and zinc pyrithione [19]. Among
the 126 candidates, a class of derivatives of the fat-soluble secosteroid vitamin D shows
activity against S. mutans. One of the vitamin D derivatives, namely calcitriol, inhibits
both planktonic cells and preforms S. mutans biofilms. Doxercalcierol, a synthetic vitamin
D2 analog, reduces pre-existing biofilms and shows synergistic effects with bacitracin,
a polypeptide that interferes with cell wall synthesis [20]. Gliptins is a common anti-
human-dipeptidyl peptidase (DPP IV) drug for the treatment of type II diabetes. X-prolyl
dipeptidyl peptidase (Sm-XPDAP) coded by the pepX gene is an analogous enzyme of DPP
IV [21]. Sm-XPDAP plays a nutritional role in S. mutans [22]. The pepX-deficient strain
of S. mutans produces fewer biofilms, suggesting that Sm-XPDAP is a potential target for
the inhibition of S.mutans biofilms [23]. Considering the similarity between Sm-XPDAP
and DDP IV, saxagliptin has been repurposed to inhibit S. mutans, which shows potent
inhibitory effects on the biofilm formation of S. mutans [23].
Reserpine, another FDA-approved blood pressure medicine, has also been repurposed
as an efflux pump inhibitor which suppresses acid tolerance and inhibits the glycosyltrans-
ferase activity of S. mutans and thus represents a promising treatment against cariogenic
biofilms [24]. Screening drugs that target key metabolic processes is also commonly used.
Folate metabolism is important for the syntheses of DNA, RNA, and amino acids in all
organisms. Bedaquiline, an active drug firstly used to inhibit the ATP-synthase of mycobac-
teria [25], also shows a great antimicrobial activity against cariogenic bacteria in the acidic
environment. In addition, bedaquiline can effectively inhibit the biofilm proliferation of
oral pathogens, especially S. mutans [26].
Toremifene, an FDA-approved drug for the treatment of breast cancer, and zafir-
lukast, an antiasthma drug that has been approved in Europe and the USA, have also
been repurposed to inhibit the growth and biofilm formation of S. mutans [27,28]. An-
other anticancer drug napabucasin (NAP), which is in phase III clinical trials for cancer
treatment, shows antibacterial activity against Escherichia coli, Streptococcus faecalis, and
Staphylococcus aureus [29,30]. Our group repurposed NAP against oral streptococci and
found that NAP exhibits good antimicrobial activity against S. mutans biofilms [31]. In
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treatment, shows antibacterial activity against Escherichia coli, Streptococcus faecalis, and
treatment, shows
treatment,
Staphylococcus showsaureusantibacterial
antibacterial
[29,30]. Our activity
activity
group against
against Escherichia
Escherichia
repurposed NAPcoli, coli,
coli, Streptococcus
Streptococcus
against faecalis, and
faecalis,
oral streptococci and
and
treatment,
treatment, shows
shows antibacterial
antibacterial activity
activity against
against Escherichia
Escherichia coli, Streptococcus
Streptococcus faecalis,
faecalis, and
and
Staphylococcus
Staphylococcus
found thatshows
treatment, NAP aureus
aureus
exhibits[29,30].
[29,30].
antibacterial good Our
Our group
group
antimicrobial
activity repurposed
repurposed
against activity
EscherichiaNAP
NAP
against against
against
coli, S. oral
mutans
Streptococcus streptococci
oral streptococci
streptococci
biofilms
faecalis, [31]. and
and In
Staphylococcus
Staphylococcus aureus
aureus [29,30].
[29,30]. Our
Our group
group repurposed NAP against oral and
found addition,
that NAP by using
exhibits NAP
good as a lead repurposed
antimicrobial compound,activity NAP
weagainst against
designed S. a oral
novel
mutans streptococci
small molecule,
biofilms [31].and In namely
found
found
found that
addition,
Staphylococcus
that
that by NAP
using
NAP
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aureus NAP
exhibits
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[29,30].good
gooda
good lead
Our antimicrobial
compound,
group
antimicrobial
antimicrobial weactivity
repurposed designed
activity
activity against
NAP
againsta
against novelS.
against
S. mutans
small
oral
mutans
S. mutans biofilms
molecule,
streptococci
biofilms
biofilms [31]. [31].
namely
[31]. and In
In
In
addition, LCG-N25,
by using which
NAP asexhibits
a lead a good antibacterial
compound, we activity
designed a and
novel low
small cytotoxicity
molecule, and induces
namely no
addition,
LCG-N25,
found
addition,that
addition, byNAP
by
by using
which
using
using NAPas
exhibits
exhibits
NAP
NAP asgood
as aaalead
lead
good
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compound,
compound, wewe
we designed
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and
against novel
low
novel smallmolecule,
S. mutans
small
small molecule,
cytotoxicitybiofilms
molecule, namely
andnamely
induces
[31].
namely In
LCG-N25, drug resistance
which exhibits of cariogenic S. mutans [32]. Repurposing existing antimicrobial drugs or
LCG-N25,
no drug by
addition,
LCG-N25,
LCG-N25, which
resistance exhibits
usingexhibits
which
which NAP
exhibits as aaaaagood
of cariogenic good
good
lead
good S. antibacterial
antibacterial
mutans[32].
compound,
antibacterial
antibacterial
activity
activity
Repurposing
weactivity
designed
activity
and
and
and
and
low
low
a novel
low
low
cytotoxicity
cytotoxicity
existing
smallantimicrobial
cytotoxicitymolecule,
cytotoxicity
andnamely
and
and
and
induces
induces
drugs
induces
induces
no drug
drug antimicrobial
resistance groups
of cariogenic
cariogenic is also
S. a promising
mutans[32]. approach
Repurposing to the control
existing of S.
antimicrobialmutans. drugsNitrofuran
no
noor
LCG-N25,
no drug
drug resistance
antimicrobial
which exhibits
resistance
resistance of
groups
of
of aisgood
cariogenic
cariogenic also S.
S. mutans[32].
amutans[32].
promising
antibacterial
S. mutans[32]. Repurposing
approach
activity
Repurposing
Repurposing and low toexisting
the antimicrobial
control
cytotoxicity
existing
existing of
and
antimicrobial
antimicrobial drugs
S. induces
mutans.
drugs
drugs
or has
antimicrobial been reported
groups to
is inhibit
also a oral bacteria
promising such as S. mutans
approach to the and Enterococcus
control of S. faecalis [33,34].
mutans.
or
no
or
or antimicrobial
Nitrofuran
drug
antimicrobial
antimicrobial has been
resistance groupsreported
of cariogenic
groups
groups is also
isis also
also aaamutans[32].
toS.inhibit promising
promising
promising approach
oral bacteria
Repurposing
approach
approach suchto to
as
to the
existing
the
the control
S. mutans and of Enterococcus
antimicrobial
control
control of
of S. mutans.
S.
S. mutans.
drugs
mutans.
orNitrofuran
Nitrofuran
faecalis
Based hason
has
[33,34].
antimicrobial been
the antimicrobial
been
Based
groups reported
reported
on the
is to inhibit
to
activity
inhibit
antimicrobial
also a promising
of bacteria
oral
oral
nitrofuran
bacteria
activity
approachof
against
such
such as
nitrofuran
to S.S.
asthe
S.
mutans,
mutans
mutans
against
control and
our
and
S.
of
group
Enterococcus
Enterococcus
mutans,
S. mutans.
synthesized
our
Nitrofuran
Nitrofuran has
has been
a novel been reported
reported
water-soluble to
to inhibit
hybridinhibit oral bacteria
oralactivity
bacteriaof
of indolin-2-one such
such
and as
as S.S. mutans
nitrofuran, mutans and
and
ZY354, Enterococcus
Enterococcus
which shows
faecalis
faecalis
group
Nitrofuran [33,34].
[33,34].
synthesized
has Based
Based
been a on
on
novel
reported the
the antimicrobial
antimicrobial
water-soluble
to inhibit activity
hybrid
oral bacteriaof of nitrofuran
nitrofuran
indolin-2-one
such as S. against
against
and
mutans S.
S. mutans,
mutans,
nitrofuran,
and ZY354,
Enterococcus our a good
our
faecalis
faecalis [33,34].
[33,34]. Based
Based
antimicrobial on
on the
the
activity antimicrobial
antimicrobial
and selectivity activity
activity
against of
of
S. nitrofuran
nitrofuran
mutans against
[35]. against
Small S.
S. mutans,
mutans,
molecules our
our
identified by
group synthesized
group synthesized a novel
novel water-soluble hybrid of of
indolin-2-one and nitrofuran, ZY354,
which
faecalis
group
group shows aBased
[33,34].
synthesized
synthesized
drug
goodaaanovel
repurposing
on
novel the water-soluble
antimicrobialantimicrobial
water-soluble
water-soluble
are summarized
activityhybrid
andof
activity
hybrid
hybrid
in Table
of
of indolin-2-one
selectivity
indolin-2-one
indolin-2-one
1.
against
nitrofuran and
against
and
and nitrofuran,
S.nitrofuran,
mutans [35].
S. mutans,
nitrofuran, ZY354,
Small
ZY354,our
ZY354,
whichsynthesized
which shows
shows a good
good antimicrobial activity and selectivity against S.nitrofuran,
mutans [35].[35]. Small
Small
molecules
group
which
which shows
shows aaa good
identified
good byantimicrobial
a novel drug
antimicrobial
antimicrobial repurposing
water-soluble activity
activity
activity areand
hybrid
and
and selectivity
summarized
of indolin-2-one
selectivity
selectivity against
in Table
against
against and S.
S.1.
S. mutans
mutans
mutans [35].ZY354,
[35]. Small
Small
molecules
molecules
which shows identified
identified
a good by
by drug
drug
antimicrobial repurposing
repurposing activity are
are
and summarized
summarized
selectivity in
in Table
Table1.
against 1.
1. mutans [35]. Small
S.
molecules
molecules identified
Table
identified by
1. Small
by drug
drug repurposing
moleculesrepurposing identifiedare
are summarized
by drug in
repurposing.
summarized in Table
Table 1.
Table 1.
molecules Small molecules
identified by drugidentified
repurposing by drug arerepurposing.
summarized in Table 1.
Small Molecules Table 1.1.Small
Chemical
Table Small moleculesidentified
Structure
Small molecules identifiedby
bydrug
drugrepurposing.
repurposing.
Mechanisms References
Small Molecules Table
Table 1.1.
Chemical Smallmolecules
moleculesidentified
Structure identifiedby
bydrug
drugrepurposing.
repurposing.
Mechanisms References
Small Molecules Table 1. SmallStructure
Chemical molecules identified by drug repurposing.
Mechanisms References
Small Molecules
Small Chemical Structure Mechanisms References
SmallMolecules
Molecules Chemical
ChemicalStructure
Structure Mechanisms
Mechanisms References
References
Small Molecules Chemical Structure Mechanisms References

Inhibit
Inhibit cariogenic
cariogenic bacteria
bacteria in an
in an acidic
acidic environment
Bedaquiline
Bedaquiline and Inhibit
environment
inhibit
Inhibit cariogenic
and inhibit bacteria
(Streptococcus
cariogenic bacteria inan
mutans)
in anS.
(Streptococcus acidic
mutans
mutans)
acidic S.
biofilm [26] [26]
Inhibit
Inhibitcariogenic
cariogenic bacteria
bacteria in
inan
anacidic
acidic
Bedaquiline
Bedaquiline environment
environment andinhibit
mutans
and inhibit
biofilm (Streptococcus
proliferation
proliferation
(Streptococcus mutans)S.
mutans) S. [26]
[26]
Bedaquiline
Bedaquiline Inhibit cariogenic
environment
environment and
andinhibit
inhibitbacteria in an acidic
(Streptococcus
(Streptococcus mutans)
mutans)S.
S. [26]
[26]
mutans
mutans biofilm proliferation
biofilmproliferation
proliferation
Bedaquiline environment and inhibit
mutans
mutans biofilm(Streptococcus
biofilm proliferationmutans) S. [26]
mutans biofilm proliferation

Inhibit the planktonic growth of S. mutans; inhibit

Biapenem Inhibit
Inhibit
S.
Inhibit thethe
mutans
the planktonic
planktonic
biofilms
planktonic growth
growth
formation
growth ofand
of S.mutans;
of
S. mutans;
S.reduce
mutans;inhibit
theinhibit S. [19]
inhibit
Inhibit
Inhibit the
theplanktonic
planktonic growth
growthof ofS.S.mutans;
mutans; inhibit
inhibit
Biapenem
Biapenem mutans
S. mutans
S.viability biofilms
biofilms formation
formation
of pre-existing and and reduce
reduce thethe [19]
viability [19] [19]
Biapenem
Biapenem
Biapenem Inhibit
S. mutans
mutans
S.viability
mutans
biofilms
the planktonic
biofilms
biofilms growthS.ofmutans
formation
formation
formation
and
and
and
biofilms
reduce
S. mutans;
reduce
reduce
the
inhibit
the
the [19]
[19]
of
ofpre-existing
pre-existing S.S.mutans
mutans biofilms
biofilms
Biapenem viability
S.viability
mutans of of pre-existing
biofilms S. mutans
formation biofilms
and reduce the [19]
viability ofpre-existing
pre-existing S.
S.mutans
mutans biofilms
biofilms
viability of pre-existing S. mutans biofilms

Inhibit the planktonic growth of S. mutans; inhibit

Cefdinir Inhibitthe
the planktonic growthof ofS.
S.mutans;
mutans;inhibit
inhibit [19]
Cefdinir Inhibit
Inhibit thethe
Inhibit biofilm
planktonic
planktonic
the formation
growth
growth
planktonic of
growthS. mutans
mutans;
of inhibit
S. mutans; [19]
inhibit [19]
Cefdinir
Cefdinir
Cefdinir Inhibit the planktonic
thebiofilm growth
biofilmformation
formationof of S.
ofS. mutans;
S.mutans
mutans inhibit [19] [19]
Cefdinir the
Inhibit the
the planktonic
biofilm
the growth
formation
biofilm of
of
formation S.
S. mutans;
mutans
of S. inhibit
mutans [19]
Cefdinir the biofilm formation of S. mutans [19]
the biofilm formation of S. mutans

Inhibit the planktonic growth of S. mutans; reduce

Calcitriol Inhibit theplanktonic
planktonic growthS.ofmutans
S.mutans;
mutans; reduce [20]
Calcitriol the
Inhibit
Inhibit viability
the
the the of pre-existing
planktonic
Inhibit growth
growth
planktonic of
of
growth S.
S. biofilms
mutans;
of reduce
reduce
S. mutans; [20]
reduce [20]
Calcitriol
Calcitriol
Calcitriol Inhibit the planktonic
theviability
viabilityof growth
ofpre-existing of
pre-existingS. S. mutans;
S.mutans reduce
mutansbiofilms
biofilms [20] [20]
Calcitriol the
Inhibit
the the planktonic
viability of growth
pre-existing
viability of of
S. S. mutans;
mutans
pre-existing S. reduce
biofilms
mutans biofilms [20]
Calcitriol the viability of pre-existing S. mutans biofilms [20]
the viability of pre-existing S. mutans biofilms

Inhibit the planktonic growth of S. mutans; inhibit

Doxercalciferol Inhibit
Inhibit theplanktonic
the S.the
the planktonic
mutans biofilms growth
formation
growth ofofS.
S.and
mutans;
reduce
mutans; inhibit
the
inhibit [20]
Inhibit
Inhibit theplanktonic
planktonic growth
growth of
ofS. mutans;
S.ofmutans; inhibit
inhibit
Doxercalciferol theInhibit
S. the biofilms
mutans planktonic growth
formation S. reduce
and mutans; inhibit [20]
the
Doxercalciferol
Doxercalciferol Inhibit
the viability
theS.
S.mutans
mutans
the of pre-existing
biofilms
planktonic
biofilms growth S.ofmutans
formation
formation S. and
and biofilms
reduce
mutans;
reduce the
inhibit
the [20]
[20]
Doxercalciferol
Doxercalciferol the viability
S.the
mutans ofbiofilms
S. mutans formation
biofilms
pre-existing and and
formation
S.mutans
mutans reduce the the [20]
reduce
biofilms [20]
Doxercalciferol viability
theviability
S. mutans of pre-existing S. biofilms
viability ofbiofilms
of
viability formation
pre-existing
pre-existing S. S.and
S.mutans
of pre-existingmutans reduce
biofilms
biofilms
mutans the
biofilms [20]
viability of pre-existing S. mutans biofilms

Inhibit both the planktonic cells and biofilms

LCG-N25 Inhibitboth
bothformation
theplanktonic
planktonic cellsand
andbiofilms
biofilms [32]
Inhibit
Inhibit the of S. cells
mutans
cells
LCG-N25
LCG-N25
LCG-N25 Inhibitboth
boththetheplanktonic
planktonic
formation of S. cellsand
mutansandbiofilms
biofilms [32]
[32]
[32]
LCG-N25 Inhibit formation
bothformation of S.mutans
the planktonic
of mutans
cells cells
and biofilms [32]
LCG-N25
LCG-N25
Inhibit both
formation ofS.
the planktonic
S. mutans and biofilms [32] [32]
formation of S. of
formation mutans
S. mutans
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Napabucasin
Napabucasin Inhibit
Inhibit S. mutans
S. mutans biofilms
biofilms [31] [31]
Napabucasin
Napabucasin Inhibit
Inhibit S. mutans biofilms [31]
Napabucasin Inhibit S.
S. mutans
mutans biofilms
biofilms [31]
[31]
Napabucasin Inhibit S. mutans biofilms [31]
Napabucasin Inhibit S. mutans biofilms [31]

Suppress acid tolerance; inhibit the

Reserpine Suppress acid acid
Suppress
Suppress tolerance; inhibit
tolerance; the
inhibit the [24]
Reserpine
Reserpine
Reserpine Suppress acid
acid tolerance;
glycosyltransferase inhibit
activity
tolerance; inhibit the
of S. mutans
the [24]
[24] [24]
Reserpine glycosyltransferase
glycosyltransferase
Suppress acid
glycosyltransferase activity
activity
tolerance;
activity of S.of S.
mutans
inhibit
of themutans [24]
Reserpine Suppress acid tolerance;
glycosyltransferase of S.
S. mutans
activityinhibit the
mutans [24]
Reserpine glycosyltransferase activity of S. mutans [24]
glycosyltransferase activity of S. mutans

Saxagliptins Reduce S. mutans biofilm formation [23]

Saxagliptins
Saxagliptins
Saxagliptins Reduce S.
Reduce
Reduce S. mutans biofilm
S. mutans formation
biofilm formation [23] [23]
Saxagliptins Reduce S. mutans
mutans biofilm
biofilm formation
formation [23]
[23]
Saxagliptins Reduce S. mutans biofilm formation [23]
Saxagliptins Reduce S. mutans biofilm formation [23]

Inhibit the growth and biofilm formation of

Toremifene Inhibit
Inhibit the
the growth and and
biofilm formation of [27]
Toremifene
Toremifene
Toremifene Inhibit the growth
Inhibit growth S.and
the growth
and biofilm
mutans
biofilm formation
biofilm
formation of
formation
of of [27]
[27] [27]
Toremifene Inhibit the growthS.
S. and
mutans
S. biofilm
mutans
mutans formation of [27]
Toremifene Inhibit the growth S.and biofilm formation of
mutans [27]
Toremifene S. mutans [27]
S. mutans

Zinc pyrithione [19]

Zinc
Zinc pyrithione [19]
Zinc pyrithione
pyrithione [19]
[19]
Zinc pyrithione
Zinc pyrithione [19] [19]
Zinc pyrithione [19]
Inhibit S. mutans planktonic cells; inhibit biofilm
Inhibit
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S. mutans planktonic cells; inhibit biofilm
Zafirlukast Inhibit S. mutans
formation
mutans planktonic
and reduce the
planktonic cells; inhibit
inhibitofbiofilm
viability
cells; the
biofilm [28]
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Inhibit
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mutans
formation
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reduce
S. mutans thecells;
biofilms
planktonicof inhibit
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mutans
viability of biofilm
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inhibit [28]
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formation and biofilms
preformed reduce
biofilms of
the
of S. mutansof the
viability
S. [28]
Zafirlukast
Zafirlukast formation andreduce
preformed
formation and reduce
biofilmsthe
the of S. mutans
viability ofofthe
mutans
viability thepreformed [28] [28]
preformed biofilms of S. mutans
preformedbiofilms
biofilmsofofS.S.mutans
mutans
Inhibit S. mutans growth and selectively inhibit
ZY354 Inhibit
Inhibit S. mutans growth and selectively inhibit [35]
ZY354
ZY354 Inhibit S.
themutans
S. biofilm
mutans growth
growth and
and selectively
formation of S. mutansinhibit
selectively inhibit [35]
[35]
ZY354 Inhibitthe
S.
the biofilm
mutans
biofilm formation
growth of
and
formation of S. mutans
selectively
S. mutans inhibit [35]
ZY354 Inhibit S. S.
the
Inhibit mutans
biofilm
mutansgrowth and
formation
growth ofselectively
and S. mutansinhibit
selectively inhibit the [35]
ZY354
ZY354 the biofilm formation of S. mutans [35] [35]
biofilm
the biofilm formation
formation S. S.
of of mutans
mutans

3. Screening from the Small-Molecule Library

3.
3. Screening from the Small-Molecule Library
3. Screening
Screening
Phenotypic
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approaches.
approaches.
commonly
screened byused
S. mutans in in silico
culture-based
colonizes on screening.
approaches.
the tooth surface Besidesand in silico
formsscreening,
biofilms, small
whichmolecules
not only elevatescan be
screened
S.
S. by culture-based
mutans
mutans colonizes
colonizes on
on approaches.
the
the tooth
tooth surface
surface and
and forms
forms biofilms,
biofilms, which
which not
not only
only elevates
elevates
screened by culture-based
S. mutans
its virulence, colonizes
but onapproaches.
also protectsthe tooth
it from surface
externalandinfluence
forms biofilms,
such aswhich not onlytreatment
antimicrobial elevates
its
its S. mutans
virulence,
virulence, but
butcolonizes
also
also on theit
protects tooth
from surface
external and forms biofilms,
influence such as which not only
antimicrobial elevates
treatment
its S.Key
mutans
virulence,
[38]. but
factors suchprotects
colonizes
also theit
asonantigens
protects from
ittooth
fromI/II,external
surface
external and influence
influence
glucosyltransferases such
forms biofilms, as
as antimicrobial
such(Gtfs),which not only
antimicrobial
sortase treatment
elevates
treatment
A (SrtA), and
its virulence,
[38]. Key factors butsuch
also asprotects it from external influence such as antimicrobial treatment
[38].
its
[38].
quorumKey
virulence,
Key sensing but such
factors
factors also
such as
as
antigens
antigens
(QS)protects
antigens
systems itare I/II,
I/II,
from
I/II,
glucosyltransferases
glucosyltransferases
external influence
glucosyltransferases
essential for S. mutans such(Gtfs),
(Gtfs), sortase
sortase
as antimicrobial
(Gtfs),
biofilms sortase
formation
A
A (SrtA),
A (SrtA),
treatment
(SrtA),
and
and
and
[39,40,41].
[38]. Keysensing
quorum factors (QS)such systems
as antigens I/II, glucosyltransferases (Gtfs), sortase A (SrtA), and
[38]. Keysensing
quorum
quorum factors (QS)
sensing such systems
(QS) as antigens
systems
are
are essential
essential
are I/II,
for
for
for S.
S. mutans
S. mutans
glucosyltransferases
essential
biofilms
mutans biofilms
biofilms
formation
formation
(Gtfs), sortase
formation
[39,40,41].
[39,40,41].
A (SrtA),
[39,40,41].and
quorum sensing (QS) systems are essential for S. mutans biofilms formation [39,40,41].
Pathogens 2021, 10, 1540 5 of 16

used in in silico screening. Besides in silico screening, small molecules can be screened by
culture-based approaches.
S. mutans colonizes on the tooth surface and forms biofilms, which not only elevates its
virulence, but also protects it from external influence such as antimicrobial treatment [38].
Key factors such as antigens I/II, glucosyltransferases (Gtfs), sortase A (SrtA), and quorum
sensing (QS) systems are essential for S. mutans biofilms formation [39–41]. Screening
small molecules against these biofilm-related factors is a promising strategy to identify
new drugs that inhibit S. mutans. S. mutans adheres to the oral surface via two mechanisms,
i.e., sucrose-independent and sucrose-dependent [42]. The sucrose-independent adhesion
is mainly mediated by antigens I/II, which is also known as PAc [43–45], while the sucrose-
dependent adhesion is mainly mediated by Gtfs including GtfB, GtfC, and GtfD [46], which
also mediate the interspecies coaggregation and play a critical role in the development
and maturation of oral biofilms [47,48]. Rivera-Quiroga et al. screened 883,551 molecules
from the library “Small” and identified three molecules, namely ZINC19835187 (ZI-187),
ZINC19924939 (ZI-939), and ZINC 19924906 (ZI-906), which inhibit S. mutans adhesion on
polystyrene microplates by targeting antigens I/II [49]. Chen et al. screened a library of
oxazole derivatives and identified a molecule called 5H6[2-(4-chlorophenyl)-4-{[(6-methyl-
2-pyridinyl)amino]methylene}-1],3-oxazole-5(4H)-1, which is able to reduce the production
of EPSs and inhibit S. mutans biofilms by inhibiting GtfC and GtfB [50]. Wu et al. screened
a small-molecule library of 506 compounds and identified an active molecule, namely
2A4, which selectively inhibits S. mutans in multispecies biofilms modestly and inhibits
both S. mutans planktonic cells and single-specie biofilms by downregulating virulence
genes and inhibiting the production of antigens I/II and Gtfs [51]. The same group by
using a structure-based virtual screening of 500,000 compounds against the GtfC cat-
alytic domain identified a lead compound G43, which selectively bonds GtfC and thus
inhibits the biofilm formation and cariogenicity of S. mutans [52]. Ren et al. also screened
15,000 molecules based on the structure of the S. mutans GtfC protein domain and found
a quinoxaline derivative,2-(4-methoxyphenyl)-N-(3-{[2-(4-methoxyphenyl)ethyl]imino}-
1,4-dihydro-2-quinoxalinylidene)ethanamine, which selectively bonds GtfC, reduces the
synthesize of insoluble glucans and biofilms of S. mutans and thus inhibits the development
of caries in vivo [53]. SrtA is a membrane-bound transpeptidase that anchors antigens
I/II to the cell wall and thus contributes to the biofilm formation of S. mutans [41,54].
Samanli et al. screened 178 small molecules from a library and identified a SrtA inhibitor,
namely CHEMBL243796 (kurarinone), which shows better a binding affinity with SrtA
than CHX and exhibits a better pharmacokinetic activity toward S. mutans [55]. Luo et al.
screened the ZINC library and the TONGTIAN library and identified several potential
inhibitors of SrtA including benzofuran, thiadiazole, and pyrrole, which are able to bind
to and inhibit SrtA. These SrtA inhibitors are promising for the control of S. mutans
biofilms [56]. The QS system is a communication system that regulates S. mutans bio-
logical behaviors such as biofilm formation and dispersal [57,58]. Ishii et al. screened
164,514 small molecules against the peptidase domain of ComA, a key component of
S. mutans QS, and identified 6 compounds that inhibit biofilm formation without repress-
ing the cell proliferation of S. mutans [59].
Acid tolerance is another important phenotypic trait associated with the cariogenicity
of S. mutans [60]. The proton pump F1F0-ATPase (H+ -ATPase) is an important enzyme
in the acid tolerance of S. mutans [61]. Sekiya et al. screened F1F0-ATPase inhibitors
against S. mutans and found that piceatannol, curcumin, and desmethoxycurcumin (DMC;
a curcumin analog) show marked activity against F1F0-ATPase of S. mutans and thus inhibit
its growth and survival in acidic conditions, suggesting a potential anticaries strategy by
inhibiting F1F0-ATPase [62].
In addition to the aforementioned molecules that have been proven to inhibit spe-
cific factors associated with the cariogenicity of S. mutans, an increasing number of small
molecules have also been screened and identified to inhibit both planktonic cells and
biofilms of S. mutans. Chen et al. screened about 2600 compounds from the MCE library and
 Pathogens 2021, 10, 1540 6 of 16

identified an antagonist of a calcium-sensing receptor, namely NPS-2143, which exhibits

antimicrobial activity against methicillin-resistant S. aureus (MRSA) [63]. Further modifica-
tions of NPS-2143 yields a compound, namely II-6s, which shows a potent antimicrobial
Pathogens 2021, 10, x FOR PEER REVIEW 6 of 15
Pathogens 2021, 10, x FOR PEER REVIEW activity against both methicillin-resistant and methicillin-sensitive S. aureus [63]. Our 6 of 15
group
Pathogens 2021,
Pathogens
Pathogens 2021, 10,,, xxx FOR
2021, 10
10 FOR PEER
FOR PEER REVIEW
PEER REVIEW
REVIEW 666 ofof 15
of 15
15
Pathogens 2021,
Pathogens 2021, 10, x FOR PEER REVIEW
10, x FOR PEER REVIEW
screened the derivatives of NPS-2143 and identified a small-molecule II-6s that effectively
6 of 15
6 of 15
inhibits the growth and EPS generation of S. mutans. In addition, II-6s shows lower cytotox-
shows
shows lower cytotoxicity
icity relative
lower cytotoxicity
to CHX, significantly relative to
relative to CHX, the
inhibits
CHX, significantly
demineralization
significantly inhibitsofthe
inhibits the
tooth demineralization
enamel inducedof
demineralization ofby
shows
S. mutans
shows
tooth
shows lower
lower
enamel
lower and cytotoxicity
inducesbynoS.
cytotoxicity
induced
cytotoxicity relative
drug
relative
mutans
relative totoand
resistance
to CHX,
CHX,
CHX, in
inducessignificantly
S. mutans
significantly
no
significantly drug inhibits
after
inhibits
resistance
inhibits thein
15 passages
the
the demineralization
[64], representing
demineralization
S. mutans
demineralization after of
of
15
of
tooth
showsenamel
shows lower induced by relative
lower cytotoxicity
cytotoxicity S. mutans
relative toand
to CHX,
CHX, induces no druginhibits
significantly
significantly resistance
inhibits the in
the S. mutans after 15
demineralization
demineralization of
of
tooth
passages
tooth enamel
a promising
tooth enamel
enamel[64], induced
alternative
induced
representing
induced byS.
by
by S.amutans
to
S. mutans
the
mutans control
promising and
and
and of induces
oral
induces
alternative
induces noto
biofilms.
no
no drug
drug
the
drug Kimresistance
et al.
resistance
control
resistance of inS.
in
oral
in S.biofilms.
synthesized
S. mutansaafter
mutans
mutans after
series
after
Kim 15of
15
et
15
passages
tooth enamel
tooth [64],induced
enamel representing
induced by S.
by S.amutans
promising
mutans and alternative
and induces no
induces noto the resistance
drug
drug control
resistance of oral
in S.
in S.biofilms.
mutans after
mutans Kim15
after et
15
passages
pyrimidinone
passages
al. synthesized
passages [64],representing
[64],
[64], representing
orseries
a of aapromising
pyrimidindione-fused
representing promising
promising
pyrimidinone
a alternative
1,4-naphthoquinones
alternative
or tothe
to thecontrol
the
pyrimidindione-fused
alternative to control
control with of1,4-naphthoquinones
of
of oralbiofilms.
oral
oral biofilms.
antibacterial
biofilms. Kimet
effects
Kim
Kim et
via
et
al.
passagessynthesized
passages [64], a series of pyrimidinone
[64], representing
representing aa promising
promising alternative or pyrimidindione-fused
alternative to the
to the control
control of of1,4-naphthoquinones
oral biofilms.
oral biofilms. Kim Kim et et
al.
with
al. synthesized
pharmacophore
al. synthesized
synthesized
antibacterial a series
aa series
series
effectsof of
hybridization,
ofvia pyrimidinone
and
pyrimidinone
pharmacophore
pyrimidinone they or pyrimidindione-fused
identified some
or pyrimidindione-fused
or pyrimidindione-fused
hybridization, and derivatives
and they 1,4-naphthoquinones
with notable
1,4-naphthoquinones
they identified some
1,4-naphthoquinones bacte-
some
with
al. antibacterial
al. synthesized
synthesized effects
aa notable
series
series ofvia
of pharmacophore
pyrimidinone
pyrimidinone hybridization,
or pyrimidindione-fused
or pyrimidindione-fused identified
1,4-naphthoquinones
1,4-naphthoquinones
with antibacterial
riostatic
with
derivatives
with and
antibacterial
antibacterialwith effects
bactericidal
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effects via
viaeffects
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against
pharmacophore
bacteriostatic
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S.bactericidal
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and they
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identified in some
and sensitive
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some
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and theyS.identified
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identified both
some
derivatives
strains [65].
derivatives
resistant
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with
withSimon notable
notable
and
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[66] screened
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a library of 75
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Simon
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S. mutans
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library in
in
in both
(CDPs),
both
of
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with notable
with notable sensitive strains and
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and Simon et al.
bactericidal [66] against
effects
effects screened
against S. amutans
S. libraryin
mutans inof both
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which are
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resistant
synthetic
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strains
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strains fromSimon
[65].
[65].
[65]. microorganisms
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of
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of 75
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[67], and
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[67],
[67],
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and
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inhibit
inhibit
inhibit S. 3 compounds
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trimetrexate
S. adhesion
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adhesion with and
and selectively
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and biofilm
biofilm
biofilmand
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microorganisms Zhang et
[67],
[67], and
andscreened
identified
identified a CDPs
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that inhibit
that inhibit 100 trimetrexate
S.
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and
and biofilm
biofilmand
inhibitory
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identified
formation. 3 effects
Zhang
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compounds
Zhang etagainst
et
et al.
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screened S.selectively
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a
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containing
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containing et al.
100screened
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effects
100 trimetrexate
trimetrexate
against
trimetrexate an antibiofilm
(TMQ)
(TMQ)
mutans
(TMQ) library
analogs
analogs
[68]. Garcia
analogs and
andetof
and
identified
formation.
formation. 3Zhang
compounds
Zhang et al.
et al. with selectively
screened
screened a library
a library inhibitory
containing
containing effects
100
100 against S. mutans
trimetrexate
trimetrexate (TMQ)
(TMQ) [68]. Garcia
analogs
analogs and
and et
2-Aminoimidazole
identified
identified
al. screened
identified 333compounds
compounds
compounds
an antibiofilm(2-AI) with
with
with derivatives
selectively
selectively
library and identified
inhibitoryeffects
inhibitory
of 2-Aminoimidazole
selectively 2-Aminoimidazole
inhibitory effects a
effects small
against
against
(2-AI)
against molecule
S.mutans
S. mutans
derivatives
S. 3F1,
mutansand which
[68].
[68]. Garcia
Garcia specif-
[68].identified
Garciaet et
et
al. screened
identified
identified
ically disturbs an antibiofilm
33 compounds
compoundsS.3F1,
mutans with
with library of
selectively
selectively
biofilms without inhibitory
inhibitory
dispersingeffects
effects (2-AI)
against
against
biofilms derivatives
S.
of mutansand
S.nonmutans
mutans [68].identified
[68]. Garcia et
Garcia
Streptococci et
a
al.al.
al. screened
screened
small
screenedmolecule ananantibiofilm
an antibiofilm
antibiofilm which library
library ofof
specifically
library of 2-Aminoimidazole
2-Aminoimidazole
disturbs
2-Aminoimidazole S. mutans (2-AI)
(2-AI)
(2-AI) derivatives
derivatives
biofilms
derivatives without anddispersing
and
and identified
identified
identified
aal.and
al. small
screenedmolecule
screened
reduces andental
an 3F1,caries
antibiofilm
antibiofilm which specifically
library
library
in rats of
[16]. Small disturbs
of 2-Aminoimidazole
2-Aminoimidazole
molecules S. mutans (2-AI)
(2-AI)
screened biofilms
derivatives
derivatives
from without
molecule anddispersing
and identified
identified
libraries are
aa small
small
small
biofilms
abiofilms molecule
molecule
of
molecule
of nonmutans
nonmutans
3F1, which
3F1,
3F1, which
which
Streptococci
Streptococci
specifically
specifically
and
specifically
and reducesdisturbs
disturbs
disturbs
reduces dentalS. mutans
S.
S.
dental
mutans
mutans
caries
caries
biofilms
biofilms
in rats
biofilms
in rats [16].
[16].
without
without
Small
without
Small
dispersing
dispersing
molecules
dispersing
molecules
a small
summarized
abiofilms
small molecule
molecule 3F1,
in Table which
3F1, which2. specifically
specifically disturbs
disturbs S. mutans
S. Table
mutans biofilms without dispersing
biofilms
biofilms
screened
screened
of
of
from
of
from
nonmutans
nonmutans
molecule
nonmutans
molecule
Streptococci
Streptococci
libraries
Streptococci
libraries are
are
and
and
and reduces
reduces
summarized
reduces
summarized
dental
dental
in
dental
in
caries
caries
caries
Table 2. biofilms
2. ininrats
in rats[16].
rats without
[16].
[16]. Smalldispersing
Small
Small molecules
molecules
molecules
biofilms of
biofilms of nonmutans
nonmutans Streptococci
Streptococci and
and reduces dental
reduces dental caries
caries in rats
in rats [16].
[16]. Small
Small molecules
molecules
screened
screened
screened from
from molecule
molecule libraries
libraries are summarized
are summarized
summarized in Table
in Table
Table 2. 2.
2.
Tablefrom
screened from2. Smallmolecule
molecule
molecules libraries
libraries
screened are
arefromsummarized in
in Table
molecule libraries. Table 2. 2.
screenedTable 2. from Smallmolecule
molecules libraries
screened are fromsummarized
molecule libraries.in
Table 2. Small molecules screened from molecule libraries.
Small Table
Table
Table 2.Small
2.
2. Smallmolecules
Small moleculesscreened
molecules screenedfrom
screened frommolecule
from moleculelibraries.
molecule libraries.
libraries.
Small Molecules
Molecules Chemical
Table SmallFormula
2. Small
Chemical
Table 2. molecules screened
Formula
molecules screened from
from molecule Mechanisms
molecule Mechanisms
libraries.
libraries.
References
References
Small Molecules Chemical Formula Mechanisms References
SmallMolecules
Small
Small Molecules
Molecules ChemicalFormula
Chemical
Chemical Formula
Formula Mechanisms
Mechanisms
Mechanisms References
References
References
Small Molecules
Small Molecules Chemical Formula
Chemical Formula Specifically disturb
Specifically S. mutans
Mechanisms
disturb biofilms
S. mutans
Mechanisms in ain
biofilms mixed
a References
References
Compound 3F1 Specifically disturb S. mutans biofilms in a mixed [16]
[16]
Compound 3F1 Specifically mixed
disturb
Specifically disturb
Specifically disturb S.S. biofilm
mutans
biofilm
S.biofilm biofilms
mutans biofilms
mutans biofilms inin a mixed
in aa mixed
mixed [16]
Compound3F1
Compound
Compound 3F1
3F1 Specifically disturb
disturb S.
S. mutans
mutans biofilms in a mixed [16]
[16]
[16]
Compound 3F1
3F1 Specifically biofilm biofilms in a mixed
biofilm
biofilm [16]
Compound biofilm [16]
biofilm
Inhibit biofilm formation by inhibiting quorum
Compound 1 Inhibit
Inhibitbiofilm
biofilm formation
formation byby inhibiting
inhibiting quorum
quorum [59]
Compound 1 Inhibitbiofilm
Inhibit
Inhibit biofilmformation
biofilm formation
sensing
formation byinhibiting
systems
by
by inhibitingquorum
inhibiting quorum
quorum [59]
[59]
Compound111
Compound
Compound Inhibit biofilm sensing systems
sensing
formation systems
by inhibiting quorum [59]
[59]
[59]
Compound 11 Inhibit biofilm formation
sensing by inhibiting
systems
sensing systems
sensing systems quorum [59]
Compound sensing systems
systems [59]
sensing

Curcumin
Curcumin
Curcumin
Curcumin
Curcumin
Curcumin
Curcumin
Curcumin

Desmethoxycurcumin Inhibit F1F0-ATPase in S. mutans and inhibit

Desmethoxycurcumin Inhibit F1F0-ATPase in S. mutans and inhibit [62]
Desmethoxycurcumin
Desmethoxycurcumin InhibitF1F0-ATPase
Inhibit
Inhibit
Inhibit F1F0-ATPase
S. mutans
F1F0-ATPase
F1F0-ATPase iningrowth
in
in S.mutans
S.
S.
S. mutansand
mutans
mutans andinhibit
and
and inhibit
inhibit
inhibit [62]
Desmethoxycurcumin
Desmethoxycurcumin Inhibit S. mutans
F1F0-ATPase in growth
S. mutans and inhibit [62]
[62]
[62]
Desmethoxycurcumin
Desmethoxycurcumin Inhibit F1F0-ATPase
S. in
mutans
S. mutans
S. S. mutans
growth
mutans growth
growth and inhibit [62]
S. mutans
mutans growth
growth [62]
S.
Piceatannol
Piceatannol
Piceatannol
Piceatannol
Piceatannol
Piceatannol
Piceatannol

Inhibit S. mutans biofilm formation by selectively

G43 Inhibit S. mutans biofilm formation by selectively [52]
G43 InhibitS.
Inhibit
Inhibit S.mutans
S. mutansbinding
mutans biofilmformation
biofilm
biofilm toformation
GtfC by
formation byselectively
selectively
selectively [52]
G43
G43
G43 Inhibit
InhibitS. mutansbinding
S.S.mutans
mutans biofilm to GtfC by
formation
biofilmformation
formation by selectively [52]
[52]
[52]
G43 Inhibit biofilm
binding
binding
binding to
to GtfC by selectively
toGtfC
GtfC [52]
[52]
G43 binding to
bindingto GtfC
toGtfC
GtfC [52]
binding
Pyrimidinone or
Pyrimidinone or Bacteriostatic and bactericidal effects against
Pyrimidinoneor
Pyrimidinone
Pyrimidinone or 1,4-
pyrimidindione-fused
or Bacteriostatic and bactericidal effects against [65]
pyrimidindione-fused
or 1,4-
Pyrimidinone or Bacteriostatic
S.Bacteriostatic
mutans in both
Bacteriostatic and
and
and bactericidal
resistant effectsagainst
and sensitive
bactericidal
bactericidal effects
effects against
strains
against [65]
Pyrimidinone
pyrimidindione-fused
naphthoquinones
pyrimidindione-fused
pyrimidindione-fused 1,4-
1,4- S.Bacteriostatic
mutans in both resistant
and and sensitive
bactericidal effects strains
against [65]
[65]
naphthoquinones 1,4-
pyrimidindione-fused
pyrimidindione-fused1,4- S.Bacteriostatic
Bacteriostatic
mutans
S. mutans
S. in
mutans in
in bothand
and
both bactericidal
bactericidal
resistant
both resistant and
resistant and effects
effects
sensitive
and sensitive against
against
strains
sensitive strains
strains
[65]
[65]
[65]
pyrimidindione-fused
naphthoquinones1,4-
naphthoquinones
naphthoquinones S. mutans
S.mutans in
mutansin both
inboth resistant
bothresistant and
resistantand sensitive
andsensitive strains
sensitivestrains
strains [65]
naphthoquinones
1,4-naphthoquinones S.
naphthoquinones

ZINC19835187 (ZI-187)
ZINC19835187 (ZI-187)
ZINC19835187(ZI-187)
ZINC19835187
ZINC19835187 (ZI-187)
(ZI-187)
ZINC19835187 (ZI-187)
ZINC19835187 (ZI-187)
Inhibit S. mutans adhesion and biofilm formation by
Inhibit S. mutans adhesion and biofilm formation by [49]
InhibitS.
Inhibit
Inhibit S.mutans
S. mutans
mutans adhesion
targeting
adhesion
adhesion andbiofilm
antigens
and
and biofilm formationby
I/II formation
biofilm by
by [49]
Inhibit S. targeting
S. mutans
mutans antigens
adhesion I/II formation
and biofilm
biofilm formation by [49]
[49]
[49]
Inhibit adhesion
targeting
targeting
targeting and
antigens
antigens
antigens I/II formation by
I/II
I/II [49]
targeting antigens
antigens I/II
I/II [49]
targeting
ZINC19924939 (ZI-939)
ZINC19924939 (ZI-939)
ZINC19924939(ZI-939)
ZINC19924939
ZINC19924939 (ZI-939)
(ZI-939)
 Piceatannol
Piceatannol

Pathogens 2021, 10, 1540 Inhibit S. mutans biofilm formation by selectively 7 of 16

G43 Inhibit S. mutans biofilm formation by selectively [52]
G43 binding to GtfC [52]
binding to GtfC

Pyrimidinone or Table 2. Cont.

Pyrimidinone or Bacteriostatic and bactericidal effects against
pyrimidindione-fused 1,4- Bacteriostatic and bactericidal effects against [65]
pyrimidindione-fused 1,4- S. mutans in both resistant and sensitive strains [65]
Small Molecules
naphthoquinones Chemical Formula Mechanisms
S. mutans in both References
resistant and sensitive strains
naphthoquinones

ZINC19835187
ZINC19835187 (ZI-187)
(ZI-187)
ZINC19835187 (ZI-187)
Inhibit S. mutans adhesion and biofilm formation by
Inhibit S. mutans adhesion and biofilm formation by [49]
targeting antigens I/II [49]
targeting antigens I/II

ZINC19924939 (ZI-939)
Pathogens 2021, 10
ZINC19924939
ZINC19924939 , (ZI-939)
x FOR PEER REVIEW
(ZI-939) Inhibit S. mutans adhesion and biofilm 7 of 15
Pathogens 2021, 10, x FOR PEER REVIEW [49] 7 of 15
Pathogens 2021, 10, x FOR PEER REVIEW formation by targeting antigens I/II 7 of 15
Pathogens 2021, 10, x FOR PEER REVIEW 7 of 15
Pathogens 2021, 10, x FOR PEER REVIEW 7 of 15

ZINC
ZINC 19924906
19924906 (ZI-906)
(ZI-906)
ZINC 19924906 (ZI-906)
ZINC 19924906 (ZI-906)
ZINC 19924906 (ZI-906)
ZINC 19924906 (ZI-906)

Inhibit S. mutans adhesion and biofilm formation by

Inhibit S. mutans
Inhibit adhesion
S.antigens
mutans adhesionandandbiofilm formation by
biofilm
2A4 targeting
Inhibit S. mutans I/II and
adhesion andglucosyltransferases
biofilm formation by [51]
2A42A4 targeting
formation
Inhibit antigens
by
S. mutans I/II
targeting
adhesion and glucosyltransferases
antigens
and I/II
biofilm and
formation [51]
by [51]
2A4 targeting antigens I/II and
(Gtfs) glucosyltransferases [51]
Inhibit S. glucosyltransferases
mutans ((Gtfs)
adhesion
targeting antigens I/II (Gtfs)
and glucosyltransferasesby
and biofilm formation
2A4 Gtfs) [51]
2A4 targeting antigens I/II and glucosyltransferases [51]
(Gtfs)
(Gtfs)
2-(4-methoxyphenyl)-N-(3-{[2-
2-(4-methoxyphenyl)-N-(3-{[2-
(4-methoxyphenyl)ethyl]imino}-
2-(4-methoxyphenyl)-N-(3-{[2-
2-(4-methoxyphenyl)-N-(3-{[2-(4- Inhibit the biofilm
Inhibit formation
the biofilm and destroy
formation and mature
(4-methoxyphenyl)ethyl]imino}- Inhibit the biofilm formation and destroy mature [53]
2-(4-methoxyphenyl)-N-(3-{[2-
1,4-dihydro-2-
(4-methoxyphenyl)ethyl]imino}-
methoxyphenyl)ethyl]imino}-1,4- biofilms
Inhibitwithout killing
the biofilm S. mutans
formation
destroy mature by
and inhibiting
destroy GtfC
mature [53]
1,4-dihydro-2-
2-(4-methoxyphenyl)-N-(3-{[2- biofilms without killing S. mutans bydestroy
inhibiting [53]
GtfC [53]
(4-methoxyphenyl)ethyl]imino}-
quinoxalinylidene) ethanamine
dihydro-2-quinoxalinylidene)
1,4-dihydro-2- Inhibit the biofilm
biofilms
biofilms without
without formation
killing
killing and
S. mutans
S. mutans by mature
by inhibiting GtfC
quinoxalinylidene) ethanamine
(4-methoxyphenyl)ethyl]imino}- Inhibit the biofilm formation and destroy mature [53]
1,4-dihydro-2-
ethanamine
quinoxalinylidene) ethanamine biofilms without killing S.GtfC
inhibiting mutans by inhibiting GtfC [53]
1,4-dihydro-2-
quinoxalinylidene) ethanamine biofilms without killing S. mutans by inhibiting GtfC
quinoxalinylidene) ethanamine Inhibit growth and exopolysaccharides (EPS)
Inhibit growth and exopolysaccharides (EPS)
Inhibit growthgeneration of S. mutans;
and exopolysaccharides (EPS)
II-6s Inhibit generation
growth and of S. mutans;
exopolysaccharides [64]
II-6s Inhibit
inhibit thegrowth and exopolysaccharides
demineralization
generation of S. of tooth enamel
mutans; (EPS)
and [64]
II-6s inhibit (EPS)
Inhibitthe generation
demineralization
growth and of S. of
mutans;
tooth enamel
exopolysaccharides and
(EPS) [64]
induce
inhibit generation of
no drug resistance
the demineralization S. mutans;
in S. mutans
of tooth enamel and
II-6s II-6s inhibit
induce thegeneration
nodemineralization
drug resistance of
in
of S. mutans; tooth
S. mutans [64] [64]
II-6s inhibit the demineralization
induce no drugno resistanceof tooth enamel and
in S. mutans [64]
enamel and
inhibitinduce induce
the demineralization drug resistance
of tooth in
no S.
drug resistance
mutans in S. enamel
mutans and
Inhibit
inducethenobiofilm
drug formation
resistance of in S.
S. mutans
mutans by
5H6 Inhibit the biofilm formation of S. mutans by [50]
5H6 antagonizing
Inhibit the biofilm formation Gtfsof S. mutans by [50]
5H6 antagonizing Gtfsof S. mutans by [50]
Inhibit the biofilm formation
antagonizing Gtfs
5H6 Inhibitthe
Inhibit thebiofilm
biofilm formation
formation ofofS.S. mutans by
mutans [50]
5H65H6 antagonizing Gtfs [50] [50]
by antagonizing
antagonizingGtfs Gtfs
4. Screening from Natural Products
4. Screening from Natural Products
4. Screening from Natural
Natural products are anProducts
ample resource of drugs because of their structural diversity
Natural products
4. Screening are anProducts
from Natural ample resource of drugs because of their structural diversity
and
4. Natural
biological
Screening products
activity
from are
[69].
Natural an ample resource
Natural
Products productsofand drugs theirbecause of theiraccounted
derivatives structuralfor diversity
about
and biological
Natural activity [69]. Natural productsofand their derivatives accounted for about
32%
4. Screeningof from products
and biological
small-molecule
Natural are
activityProducts
[69]. anNatural
drugs ample
whichresource
products
are approved drugs
and theirbecause
being on of
derivatives
thetheir structural
accounted
market fromfor diversity
about
1981 to
32% Natural
of
and biological products
small-molecule
activityare an
drugs
[69]. ample
which
Natural resource
are
products of drugs
approved
andfor because
being
their on of their
the
derivatives structural
market
accounted from diversity
1981
for to
about
32%
Naturalof
2019[70]. small-molecule
Natural
products products
are drugs
an[69].
ample which
provide a
resource are
large approved
library
of drugs becausebeing
the on the
identification
of market
their structural of from 1981
antimicrobials
diversity to
and biological
2019[70].
32% lower Natural activity
products
of small-molecule drugsNatural
provide
which aproducts
large and
library
are approved their
for the derivatives
being identification accounted
on the market of for about
antimicrobials
from 1981 to
2019[70].
with
and biological Natural products
cytotoxicity.
activity [69]. Naturalprovide a
products large library for the
and their derivatives identification
accounted of antimicrobials
for about
32%
with of small-molecule
lower
2019[70]. cytotoxicity.
Natural productsdrugs which
provide a are
largeapproved
library for being on the
the identificationmarket from 1981 to
of antimicrobials
with lower
Tea
32% 2019[70]. cytotoxicity.
(Camellia
of small-molecule sinensis)
drugs has many health benefits with antimicrobial, anti-
withTea Natural
lower(Camellia sinensis) has many health benefits with antimicrobial,to anti-
products
cytotoxicity.
which
provide area approved
large library being
for on
the the market
identification from
of 1981
antimicrobials
2019 with Tea
inflammatory,
[70]. lower (Camellia
Natural and
products sinensis) has
cancer-preventive
provide many
a large library health
activity benefits
[71,72].
for the identification with
The antimicrobial,
tea polyphenols anti-
inflammatory, cytotoxicity.
Tea (Camellia and sinensis)
cancer-preventive
has many activity
health [71,72]. with
benefits Theofantimicrobial,
antimicrobials
tea polyphenols anti-
inflammatory,
epigallocatechin
with epigallocatechin
lower cytotoxicity. and
gallate cancer-preventive
(EGCG) has shown activity
antimicrobial [71,72]. The
activity tea
against S.polyphenols
mutans for
Tea (Camellia
inflammatory, and sinensis)
gallate (EGCG) hashasmany
cancer-preventive shownhealth benefits
antimicrobial
activity with
activity
[71,72]. The antimicrobial,
against
tea mutansanti-
S.polyphenols for
epigallocatechin
decades.
Tea (CamelliaEGCG gallate
can
sinensis) has (EGCG)
inhibit
manythethe has shown
virulence
health benefits antimicrobial
of
withS. mutans activity
including
antimicrobial, against
acid S. mutans
production,
anti-inflammatory, for
inflammatory,
decades. EGCG
epigallocatechin and
can
gallatecancer-preventive
inhibit
(EGCG) virulence
has shown activity
of S. [71,72].
mutans
antimicrobial The
including
activity tea
acid
against polyphenols
production,
S. mutans for
decades. EGCG
aciduricity, and biofilm
and cancer-preventive can inhibit the
formation.
activity(EGCG)
[71,72]. The virulence
EGCG
tea of S.
can reduce
polyphenols mutans including
acid production
epigallocatechin acid
of S.
gallate production,
mutans by
(EGCG)
epigallocatechin
aciduricity,
decades. EGCG gallate
and biofilm
can formation.
inhibit thehasvirulence
shown
EGCG antimicrobial
can of reduce
S. acidactivity
mutans against
production
including of S.
acid S. mutans
mutans for
production, by
aciduricity,the
inhibiting and biofilm formation.
expression and activity EGCG can reduce
of lactate acid production
dehydrogenase, suppressofaciduricity
S. mutans by by
decades.
inhibiting EGCG
theand
aciduricity, can inhibit
expression
biofilm the virulence
and activity
formation. of lactate
EGCG of dehydrogenase,
can S. mutans
reduce acid including
suppress
production acid production,
ofaciduricity
S. mutans by
by
inhibiting
inhibiting Fthe expression
1F0-ATPase, and and activity
reduce the ofbiofilm
lactate dehydrogenase,
formation suppress
by inhibiting Gtfsaciduricity
activity by
and
aciduricity,
inhibiting F 1and
inhibiting FtheF biofilm
0-ATPase,
expression formation.
and andreduce EGCG
the
activity biofilmcan reduce
formation acidby production
inhibiting of
Gtfs S. mutans
activity by
and
inhibiting
downregulating 1F0-ATPase,
gtf genesand reduce
[73,74,75]. A of
the lactate
biofilm
recent dehydrogenase,
formation
study suppress
by inhibiting
investigated the effectGtfsaciduricity
activity
of EGCGand by
on
inhibiting
inhibiting the
downregulating F1F0expression
gtf genes
-ATPase, and
and activitythe
[73,74,75].
reduce Aofrecent
lactatestudy
biofilm dehydrogenase,
investigated
formation by suppress
the effect
inhibiting aciduricity
Gtfs ofactivity
EGCG and by
on
downregulating
the gtf genes
phosphoenolpyruvate-dependent [73,74,75]. Aphosphotransferase
recent study investigated
system the effect
(PEP-PTS) ofofEGCG
both onS.
inhibiting
the F1F0-ATPase, and[73,74,75].
phosphoenolpyruvate-dependent
downregulating gtf genes reduce theA biofilm formation
phosphotransferase
recent by inhibiting
system Gtfs activity
(PEP-PTS) ofof bothandS.
the
mutansphosphoenolpyruvate-dependent
and non-mutans streptococci and foundstudy
phosphotransferase investigated
that EGCG system
exhibits the effect
(PEP-PTS)
excellent EGCG
of both on
inhibitory S.
Pathogens 2021, 10, 1540 8 of 16

has shown antimicrobial activity against S. mutans for decades. EGCG can inhibit the viru-
lence of S. mutans including acid production, aciduricity, and biofilm formation. EGCG
can reduce acid production of S. mutans by inhibiting the expression and activity of lactate
dehydrogenase, suppress aciduricity by inhibiting F1 F0 -ATPase, and reduce the biofilm
formation by inhibiting Gtfs activity and downregulating gtf genes [73–75]. A recent
study investigated the effect of EGCG on the phosphoenolpyruvate-dependent phospho-
transferase system (PEP-PTS) of both S. mutans and non-mutans streptococci and found
that EGCG exhibits excellent inhibitory effects against the acid production of oral strep-
tococci [76]. Melok et al. screened and identified a lipid-soluble green tea polyphenols
based on EGCG, namely epigallocatechin-3-gallate-stearate (EGCG-S) with better stabil-
ity and an antibiofilm activity equivalent to chlorhexidine gluconate [77]. In addition,
the EGCG treatment showed lower cytotoxicity and better anti-inflammatory effects on
S. mutans-stimulated odontoblast-like cells compared with CHX [78], indicating a potential
application of EGCG to the management of dental caries.
Propolis is a hard, resinous, nontoxic natural product from plants with a history of
being used as a dietary supplement. Propolis has shown a good antimicrobial activity
against S. mutans for decades [79,80]. Koo et al. identified two small-molecule com-
pounds from propolis extracts, namely apigenin and trans-trans farnesol (tt-farnesol),
which exhibit distinguished biological activities against dental caries [81,82]. Apigenin, a
4β,5,7-trihydroxyflavone, can effectively inhibit Gtfs, specifically GtfB and GtfC. tt-farnesol,
which is the most effective antibacterial compound in propolis, can reduce cell viability by
disrupting membrane integrity and destabilizing oral biofilms rather than affecting Gtfs
activities [81,83]. Moreover, tt-farnesol can reduce the intracellular iodophilic polysaccha-
rides (IPS) accumulation of S. mutans and thus reduces the severity of smooth surface caries
in rats [81,84]. The mechanism of tt-farnesol is likely attributed to the lipophilic moiety
interaction with the bacterial membrane [84]. The combinatory use of apigenin, tt-farnesol,
and fluoride can effectively reduce the biofilms and acidogenicity of S. mutans [84]. Caffeic
acid phenethyl ester (CAPE), which is extracted from propolis, shows a broad-spectrum
antimicrobial activity against Enterococcus faecalis, S. aureus, Bacillus subtilis, Pseudomonas
aeruginosa, and other species [85]. A recent study has shown that CAPE not only affects
the thickness of S. mutans biofilms, but also inhibits its biofilm formation and maturation,
particularly by reducing EPS production [86,87].
In addition to the well-characterized tea catechins and propolis, other small molecules
obtained from natural resources have also been shown to inhibit S. mutans planktonic
cells and biofilms. He et al. showed that trans-cinnamaldehyde (TC) inhibited the acid
production and aciduricity of S. mutans and downregulated virulence genes of S. mutans
including gtfD [88]. Besides, TC showed synergistic effects with CHX on the inhibition of
S. mutans biofilms and virulence by regulating genes related to metabolism, QS, bacteriocin
expression, stress tolerance, and biofilm formation [89]. Ursolic acid has shown inhibitory
effects on the EPS synthesis and the biofilm formation of S. mutans [90,91]. Resveratrol can
inhibit the acid production, acid tolerance, and EPS production of S. mutans [92]. Ficin, a
sulfhydryl protease isolated from the latex of fig trees, can inhibit the total protein and the
biofilm formation of S. mutans and reduce the virulence of S. mutans [93]. Baicalin, another
plant-derived molecule, can reduce the sucrose-dependent biofilm formation of S. mutans
likely by inhibiting Gtfs. Baicalin can also downregulate virulence genes and inhibit the acid
production of S. mutans [94]. Piceatannol, a kind of stilbene, can target the GtfC domain,
inhibit glucans production and thus reduce S. mutans biofilm formation. Piceatannol
can also inhibit S. mutans colonization in a sucrose-dependent drosophila colonization
model [95]. β-sitosterol from Kemangi (Ocimum basilicum L.) can inhibit SrtA and thus
suppresses S. mutans biofilm formation [96]. Astilbin, a flavonoid from Rhizoma Smilacis
Glabtar, can inhibit the activity of SrtA and the biofilm formation of S. mutans without
repressing its growth [97]. Abietic acid, a natural product derived from pine rosin, also
exhibits inhibitory effects on the acid production and the biofilm formation of S. mutans [98].
Rhodiola rosea, a traditional Chinese medicine, can inhibit the biofilm formation likely
 Pathogens 2021, 10, 1540 9 of 16

via downregulating gtf genes and genes associated with the QS system of S. mutans [99].
α-mangostin (αMG) extracted from tropical plants shows antimicrobial effects against
planktonic cells of S. mutans [100] and can disrupt S. mutans biofilms by inhibiting the
enzyme activity of GtfB, GtfC, and F1F0-ATPase [101]. N-arachidonoylethanolamine (AEA),
a kind of endocannabinoids (ECs) [102], in combination with poly-L-lysine can inhibit
Pathogens 2021, 10, x FOR PEER REVIEW 9 of 15are
S.mutans biofilm formation [103]. Small molecules screened from natural products
Pathogens 2021, 10, x FOR PEER REVIEW 9 of 15
summarized in Table 3.
Pathogens 2021, 10, x FOR PEER REVIEW 9 of 15
Pathogens 2021, 10, x FOR PEER REVIEW 9 of 15
Pathogens 2021, 10, x FOR PEER REVIEW Table 3. Small molecules screened from natural products. 9 of 15
Pathogens 2021, 10, x FOR PEER REVIEWTable 3. Small molecules screened from natural products. 9 of 15
Pathogens 2021, 10, x FOR PEER REVIEWTable 3. Small molecules screened from natural products. 9 of 15
Pathogens Small 10, x FOR
2021, Molecules PEER REVIEW Chemical Formula Mechanisms 9 of 15
References
Small
Pathogens Molecules
2021, 10, x FOR PEER Chemical
REVIEWTable Formula
3. Small molecules screened from natural Mechanisms
products. References
9 of 15
Small Molecules Table 3. Small
Chemical molecules screened from natural Mechanisms
Formula products. References
Small Molecules Table 3. Small
Chemical molecules screened from natural products.
Formula Mechanisms References
Table Inhibit
3. Small molecules screened fromInhibit Gtfs,
natural specifically
Gtfs,products. GtfB and
specifically GtfB and GtfC;
GtfC;
Small Molecules Chemical
Table 3. SmallFormula
molecules screened Inhibit
from Gtfs,
natural Mechanisms
specifically
products. GtfB and GtfC; References
Apigenin
SmallApigenin and
Molecules
and Chemical
Table 3. SmallFormula
molecules screened disrupt membrane
disrupt
from natural integrity,
Mechanisms
membrane
products. integrity,destabilize
destabilize oral oral [79,80,81,82,8
References
Small Molecules
Apigenin and Chemical Formula Inhibit
disrupt Gtfs,
membrane specifically
Mechanisms
integrity, GtfB and
destabilize GtfC; oral [79–87]
References
[79,80,81,82,8
trans-trans
trans-trans farnesol
farnesol Table 3. Small molecules screened
biofilms from
biofilms
Inhibit natural
and and
reduce
Gtfs, products.
reduce the the
specifically intracellular
intracellular
GtfB iodophilic
andiodophilic
GtfC; 3,84,85,86,87]
Small Molecules
Apigenin and Chemical Formula disrupt membrane Mechanisms
integrity, destabilize oral References
[79,80,81,82,8
trans-trans
Small farnesol
Molecules Chemical Formula polysaccharides
biofilmsInhibit
polysaccharides and reduce
Gtfs, (IPS)
the
specifically
Mechanisms
(IPS) accumulation
intracellular
accumulation GtfB and of S. mutans
iodophilic
GtfC;
of S. mutans 3,84,85,86,87]
References
Apigenin
Small
trans-trans and
Molecules
farnesol Chemical Formula disrupt
biofilmsInhibit membrane
and Gtfs, integrity,
Mechanisms
specifically
reduce the GtfBdestabilize
intracellular and GtfC; oral [79,80,81,82,8
References
Apigenin and polysaccharides
disrupt
Inhibit membrane
Gtfs, (IPS) accumulation
integrity,
specifically GtfB ofiodophilic
destabilize
and S. mutans
GtfC; oral 3,84,85,86,87]
[79,80,81,82,8
trans-trans
Apigenin farnesol
and biofilms
disrupt
polysaccharides
Inhibit and reduce
membrane
Gtfs, (IPS) the intracellular
integrity,
accumulation
specifically destabilize
GtfB and iodophilic
oral
ofiodophilic 3,84,85,86,87]
[79,80,81,82,8
S. mutans 3,84,85,86,87]
GtfC;
trans-trans
Apigeninfarnesol
and biofilms
disrupt
Inhibitand reduce
membrane
Gtfs, the intracellular
integrity,
specifically GtfBdestabilize
and GtfC;oral [79,80,81,82,8
trans-trans
Apigeninfarnesol
and polysaccharides
Inhibit
biofilms
disrupt the
polysaccharides and activity(IPS)
reduce
membrane (IPS)
accumulation
ofthe
sortase
intracellular
integrity,
accumulation
( SrtA)
Adestabilizeofiodophilic
S.
and mutans
the
oral
ofiodophilic
S.and
mutans 3,84,85,86,87]
[79,80,81,82,8
trans-trans
Apigeninfarnesol
trans-trans
and
farnesol
biofilms
disrupt
Inhibit
polysaccharides
biofilms
and
the reduce
membrane
activity
andactivity (IPS)
reduce
ofthe
the
intracellular
integrity,
sortase
biofilm
accumulation A
intracellular
(
destabilize
SrtA) oral
ofiodophilic
S. the
mutans
3,84,85,86,87]
[79,80,81,82,8
Astilbin
trans-trans farnesol Inhibit
polysaccharides
biofilms
Inhibit the
and
the (IPS)
reduce
activity ofofthesortase
accumulation
sortase A (SrtA)
intracellular
A (SrtA) of
and and
S.
iodophilic
the the 3,84,85,86,87]
mutans
biofilm
[97]
3,84,85,86,87]
Astilbin
Astilbin formation
Inhibit the of
polysaccharides S. (IPS)
mutans
activity biofilm
of without
sortase
accumulation (
A repressing
SrtA)
of S.and its
the
mutans [97]
[97]
Astilbin formation
Inhibit
formation theof
polysaccharides ofS.S.mutans
(IPS)
activity biofilm
of
mutans without
accumulation
sortase
without A (repressing
repressing of S.
SrtA) itsmutans
and growth
the
its [97]
growth
biofilm
Astilbin Inhibit
formation the activity
of S. mutans of sortase
without A (repressing
SrtA) and its the [97]
Astilbin Inhibit
formation the activity
of S. mutans
growth
biofilm
of sortase
without A (repressing
SrtA) and the its [97]
Inhibit
Inhibit acidthe activity of sortase
biofilm
growth A ( SrtA) and the
Astilbin
Astilbin
formation
Inhibit theproduction
of S. mutans
activity and
biofilm
of sortase
growth
the A
without biofilm
SrtA)formation
(repressing and itsthe [97]
[97]
Abietic acid formation
Inhibit of S. mutans
acid production and
biofilm
of
growth without
the biofilmrepressing its
formation [98]
Astilbin formation
Inhibit of S.
acid production mutansbiofilm
andwithout
the biofilmrepressing its
formation [97]
Astilbin
Abietic acid formation
Inhibit acid ofproduction
S. mutans growth
S.growthofwithout
mutans
and the repressing its of [97]
[98]
Abietic
Abieticacid
acid Inhibit
formationacid production
of S. mutans and
of thebiofilm
without biofilm formation
repressingformationits [98]
[98]
Inhibit acid production S.growth
S.mutans
and
mutans the biofilm formation
Abietic acid Inhibit acid production S. of the biofilm formation
growth
and
mutans [98]
Abietic Show synergistic antibiofilm effects formation
with
AEAacid
Abietic acid
Inhibit
Show
acid production
synergistic
of
and the biofilm
S.antibiofilm
mutans
of the effectsformation
with
[98]
[103]
[98]
Inhibit acid production
poly-L-lysine S. and
aginst
mutans S. biofilm
mutans
AEAacid
Abietic Inhibit Show acid production
synergistic of
and theS.biofilm
antibiofilm effectsformation
with [103]
[98]
Abietic
AEA acid poly-L-lysine S. aginst
mutans
of mutans [98]
[103]
Abietic acid Show Show synergistic S. antibiofilm
synergistic antibiofilm
mutans
of effects
effects withwith [98]
AEA
AEA Showpoly-L-lysine
Disrupt synergistic
mutansS.
S. poly-L-lysine
aginst
antibiofilm
mutans
biofilmsaginst
S. mutans
by effects with
S.inhibiting
mutans the
[103]
[103]
AEA poly-L-lysine
Showpoly-L-lysine
synergistic aginst
S.antibiofilm
mutans S. mutans
effects with [103]
αMG Disrupt S. mutans aginst
biofilms S.and
mutans [100,101]
AEA
αMG enzyme Show synergistic
activities of GtfB, GtfC,by
antibiofilm inhibiting
effects with
F1F0-ATPase the [103]
[100,101]
AEA Disrupt
Show poly-L-lysine
S. mutans
synergistic aginstby
biofilms
antibiofilm S. mutans
inhibiting
effects withthe [103]
αMG
AEA enzyme activities
Showpoly-L-lysine
synergistic of GtfB, GtfC,
aginst by
antibiofilm and
S. mutans F1F0-ATPase
effects with [100,101]
[103]
AEA enzyme Disrupt S.
activitiesmutans
poly-L-lysine biofilms
of GtfB, GtfC,
aginst S.andinhibiting
mutans F1F0-ATPase the [103]
αMG Disrupt
Disrupt S.S.mutans
mutans
poly-L-lysine biofilms
biofilmsaginst by inhibiting
by inhibiting
S.andmutans the
the enzyme [100,101]
αMG
αMG enzyme Disrupt
Inhibit activities
S.
biofilmmutansof GtfB,
biofilms
formation, GtfC, by
acid F1F0-ATPase
inhibiting
production, the [100,101]
[100,101]
αMG enzyme Disrupt activities
activities ofof
S. mutans GtfB,
GtfB, GtfC,
biofilms GtfC, and
byandF1F0-ATPase
F1F0-ATPase
inhibiting the [100,101]
Baicalin Inhibit biofilm formation, acid production, [94]
αMG
Baicalin enzyme activities of
and GtfB,
virulenceGtfC,
Disrupt S. mutans biofilms by inhibiting the and F1F0-ATPase [100,101]
[94]
αMG enzyme Inhibit
Disrupt activities
biofilm
S. mutans of
and GtfB,
formation,
biofilms GtfC,
virulence byand
acid F1F0-ATPase
production,
inhibiting the [100,101]
Baicalin
αMG enzyme Inhibitactivities
biofilmof GtfB,
formation, GtfC, acidand F1F0-ATPase
production, [94]
[100,101]
Baicalin enzyme Inhibit biofilmand
activities of virulence
GtfB,
formation, GtfC, acidand F1F0-ATPase
production, [94]
Baicalin Inhibit biofilm and virulence
formation, acid production, [94]
Inhibit biofilm
and formation,
virulence acid production,
Baicalin
Baicalin Inhibit S. mutans biofilm formation
Inhibit biofilm formation, acid production, by inhibiting [94]
[94]
β-sitosterol from Kemangi
Baicalin Inhibit and
biofilmbiofilm and
formation,virulence
virulence acid production, [96]
[94]
Baicalin Inhibit
InhibitS. mutans
biofilm and SrtA
formation, formation
virulence acid by inhibiting
production, [94]
β-sitosterol from Kemangi
Baicalin Inhibit S. mutans biofilm and virulence formation by inhibiting [96]
[94]
β-sitosterol from Kemangi and SrtA SrtA
virulence [96]
Inhibit S. mutans biofilm formation by inhibiting
β-sitosterol from Kemangi Inhibit S. mutans biofilm formation by inhibiting [96]
β-sitosterol from Kemangi Inhibit S. mutans biofilm SrtA formation by inhibiting [96]
β-sitosterol from Kemangi SrtA
Inhibit S. mutans biofilm formation by inhibiting [96]
β-sitosterol
β-sitosterolfrom
from Kemangi
Kemangi Inhibit
InhibitS.S.mutans biofilm
mutans biofilm SrtA formation
formation byby inhibiting
inhibiting SrtA [96]
[96]
β-sitosterol from Kemangi Inhibit S. mutans biofilm SrtA formation by inhibiting [96]
β-sitosterol from Kemangi SrtA [96]
Inhibit S. mutans acid production, SrtA aciduricity, and [73,74,75,76,7
Epigallocatechin gallate (EGCG) Inhibit S. mutansbiofilm acid production,
Epigallocatechin gallate (EGCG) formation aciduricity, and [73,74,75,76,7 7,78]
Inhibit S. mutansbiofilm acid production,
formation aciduricity, and [73,74,75,76,7 7,78]
Epigallocatechin gallate (EGCG) Inhibit S. mutansbiofilm acid production, aciduricity, and [73,74,75,76,7
Epigallocatechin gallate (EGCG) Inhibit S. mutans acid production, formation aciduricity, and [73,74,75,76,7 7,78]
Epigallocatechin gallate (EGCG) Inhibit S. mutansbiofilm formation aciduricity, and [73,74,75,76,7
acid production, 7,78]
Epigallocatechin gallate (EGCG) Inhibit S. mutansbiofilm formation aciduricity,
acid production, 7,78]
and [73,74,75,76,7
Epigallocatechin gallate
Epigallocatechin (EGCG)
gallate Inhibit
InhibitS. mutans biofilm
S. mutans formation
acidproduction,
acid production, aciduricity,
aciduricity, 7,78]
and [73,74,75,76,7
and biofilm
Epigallocatechin gallate (EGCG)
(EGCG) Inhibit mutansbiofilm
InhibitS.glucans formation
acid formation
production,
production by Gtfs, aciduricity,
selectively 7,78]
[73–78]
and [73,74,75,76,7
Epigallocatechin gallate (EGCG) biofilm formation 7,78]
Piceatannol Inhibit glucans biofilm
production formation
affect S. mutans biofilms formation and inhibit by Gtfs, selectively 7,78]
[95]
Piceatannol Inhibit
affect S.glucans production by Gtfs, and selectively
Inhibit S.mutans
mutans
glucans
biofilms
colonization
production
formation
by in
Gtfs, vivo inhibit
selectively
[95]
Piceatannol affect S.glucans
Inhibit mutans
S. mutans biofilms
colonization
production formation in vivo
by Gtfs, and inhibit
selectively [95]
Piceatannol affect S.glucans
Inhibit mutans
S. mutans biofilms
production
colonization formation
by Gtfs,
in vivo and inhibit
selectively [95]
Piceatannol affect
Inhibit S.glucans
mutans biofilms
production formation
by Gtfs, and inhibit
selectively [95]
Piceatannol Inhibit
affect
Inhibit S.
acid mutans
S.glucans
mutans colonization
production
biofilms
production and
formation in
Gtfs, vivo
byaciduricity and and
inhibit
selectively [95]
Resveratrol
Piceatannol affect
Inhibit
Inhibit S. S.
acidmutans
mutans
glucans colonization
biofilms
production
production formation
and by in vivo and
aciduricity
Gtfs, inhibit
and
selectively [92]
[95]
Piceatannol
Resveratrol affect down-regulated
InhibitS. glucans
mutans
S. mutans productionvirulence
colonization
biofilms formation by Gtfs,
in genes
vivoselectively
and inhibit [95]
[92]
Piceatannol
Piceatannol Inhibit
affect affect acid
S.
mutans production
S.mutans
S.down-regulated
mutans colonization
biofilms
biofilms and
virulence aciduricity
formation
formation in genes
vivo
and
andinhibitand
inhibit [95]
[95]
Resveratrol Inhibit S.acid production
mutans colonization and aciduricity
in vivo and [92]
Resveratrol down-regulated
Inhibit S. acid S. mutans
production
mutans virulence
colonization
colonization in
and aciduricity
in genes
vivo
vivo and [92]
Resveratrol Inhibit down-regulated
acid production virulence
andgenes; genes and
aciduricity [92]
Inhibit
down-regulated virulence
Resveratrol (TC)
Trans-cinnamaldehyde Inhibit acid productionvirulence and aciduricitygenes and [92]
[88,89]
Resveratrol Inhibit acid Inhibit
down-regulated virulence
production virulence
show synergistic effects with CHX antibiofilms and genes; genes
aciduricity and [92]
Trans-cinnamaldehyde
Resveratrol (TC) Inhibit down-regulated
acid Inhibit virulence
production virulence
and genes; genes and
aciduricity [88,89]
[92]
Trans-cinnamaldehyde
Resveratrol (TC) show synergistic
down-regulated effects virulence
with CHXgenes antibiofilms [88,89]
[92]
show synergistic Inhibit virulence genes;
Trans-cinnamaldehyde (TC) Inhibiteffects
down-regulated virulence with genes;
virulenceCHXgenes antibiofilms [88,89]
Trans-cinnamaldehyde (TC) show synergistic Inhibit effects
virulence with CHX
genes; antibiofilms [88,89]
Trans-cinnamaldehyde (TC) show synergistic Inhibit effects
virulencewith genes;
CHX antibiofilms [88,89]
Trans-cinnamaldehyde (TC) Inhibit
show biofilm
synergistic formation
Inhibit effects
virulence withand maturation
CHX
genes; antibiofilms by [88,89]
Ursolic acid
Trans-cinnamaldehyde (TC) show
Inhibit synergistic
biofilmInhibit effects
formation
virulencewith and CHX antibiofilms
maturation
genes; by [90,91]
[88,89]
Ursolic acid
Trans-cinnamaldehyde (TC) show reducing
synergistic EPS with
effects production
CHX antibiofilms [90,91]
[88,89]
Inhibit biofilm formation and maturation by
 Inhibit S. mutans acid production, aciduricity, and [73,74,75,76,7
Epigallocatechin gallate (EGCG) Inhibit S.
Inhibit S. mutans
mutans acid
acid production,
production, aciduricity,
aciduricity, and
and [73,74,75,76,7
[73,74,75,76,7
Epigallocatechin gallate
Epigallocatechin gallate (EGCG)
(EGCG) biofilm formation 7,78]
biofilm formation
biofilm formation 7,78]
7,78]
Pathogens 2021, 10, 1540 10 of 16

Inhibit glucans production by Gtfs, selectively

Inhibit glucans production
Cont. glucans
Table 3.Inhibit production bybyGtfs,
Gtfs, selectively
selectively
Piceatannol affect S. mutans biofilms formation and inhibit [95]
Piceatannol
Piceatannol affect S.
affect S. mutans
mutansbiofilms
biofilms formation
formation and
andinhibit
inhibit [95]
[95]
Small Molecules Chemical Formula S. mutans colonization
Mechanisms in vivo References
S. mutans
S. mutans colonization
colonization invivo
in vivo

InhibitInhibit
acid production andand
acid production aciduricity
aciduricityand
Resveratrol
Resveratrol Inhibit acid
Inhibit acid production
production and
and aciduricity
aciduricity and [92]
[92]
Resveratrol
Resveratrol and down-regulated
down-regulated virulence
virulence genes and
genes [92]
[92]
down-regulated virulence
down-regulated virulence genes
genes

Inhibit virulence genes;

Trans-cinnamaldehyde (TC)
Trans-cinnamaldehyde (TC)
Inhibit
Inhibit
Inhibit virulence
virulence genes;
virulencegenes;
genes; [88,89]
[88,89]
Trans-cinnamaldehyde
Trans-cinnamaldehyde (TC)
(TC) show synergistic
show effects
synergistic with
withCHX
effectswith antibiofilms
CHX antibiofilms [88,89]
[88,89]
show synergistic effects
show synergistic effects with CHXCHX antibiofilms
antibiofilms

Inhibit biofilm formation and maturation by

Ursolic acid Inhibit
Inhibit biofilm
biofilm
Inhibit formation
formation
biofilm formationand
and maturation
andmaturation by
by
maturation by [90,91]
Ursolic
Ursolic acid
Ursolicacid
acid reducing EPS production [90,91]
[90,91]
[90,91]
reducing
reducing
reducing EPS production
EPSproduction
EPS production

5. Target-Based Designing
Small molecules developed by target-based designing approaches can specifically
inhibit S. mutans, which is expected to reduce the cariogenicity of oral biofilms without
significantly disturbing other commensal bacteria. Key virulence factors of S. mutans, such
as SrtA, antigens I/II, and Gtfs, are usually exploited as the targets for specific drug design.
Small molecules designed by target-based approaches are summarized in Table 4.

5.1. SrtA and Antigens I/II Inhibitor

SrtA can catalyze antigens I/II and thus initiates the subsequent sucrose-independent
adhesion and biofilm formation of S. mutans [42,54,97]. Recently, a series of SrtA inhibitors
have been identified from natural products and synthetic compounds [104,105]. Many
flavonoids have shown inhibitory effects on SrtA in Gram-positive bacteria [105]. A recent
study using molecular docking demonstrated that myricetin is able to target the binding
site of SrtA and thus inhibits SrtA activity and reduces the adhesion and biofilm formation
of S. mutans [106]. Charles et al. synthesized several peptides spanning residues 803–185
of antigens I/II and identified a synthetic peptide p1025 that is able to inhibit antigens
I/II binding to salivary receptors by forming an adhesion epitopes in a dose-dependent
way. The study showed that Q1025 and E1037 of p1025 may be the two vital residues
in the adhesion of p1025 toward antigens I/II. The effect of p1025 against S. mutans was
tested by using a Streptococcal model in vitro, and p1025 shows moderate stability and
selectivity against S. mutans recolonization to the tooth surface [107]. Li et al. also showed
that dentifrice containing p1025 is able to prevent S. mutans recolonization in vitro and
in vivo [108,109].

5.2. Gtfs Inhibitor

In the sucrose-dependent adhesion process, Gtfs synthesize EPS and allow S. mutans
to adhere to oral surfaces and coaggregate with other microbes to form biofilms [110].
Molecules specifically targeting Gtfs can inhibit S. mutans biofilm formation and are promis-
ing for caries control. Flavonols show antibiofilm activities and inhibitory effects against
S. mutans Gtfs [97,111]. Bhavitavya et al. screened a group of synthetic precursors of
flavonols which consist of 14 hydroxychalcones, and several of them exhibit selectively
effects against S. mutans biofilms. Based on compound 9 which is identified from a biofilm
assay, 9b, a Z isomer of compound 9, shows better inhibition on S. mutans. 9b as a lead
compound also exhibits selectivity against S. mutans biofilms by inhibiting Gtfs in a dose-
dependent way [112]. Wu et al. screened and identified a Gtf inhibitor, namely G43, which
showed notable effects on S. mutans biofilm formation [52]. Recently, this group further
developed 90 analogs of G43 based on the structure activity relationship (SAR) of G43 and
 Pathogens 2021, 10, 1540 11 of 16

identified several new biofilm inhibitors with enhanced potency and selectivity. Different
modifications based on G43 resulted in derivatives such as IIIA6 , IIIA8 , IIIF1 , IIIF2 , and
IIIF8 , which show an equally antibiofilm activity with G43 by inhibiting Gtfs. One of
the leads compounds, IIIF1 , selected after the comprehensive evaluation of SAR studies
and zymogram results, can also inhibit S.mutans as a Gtf inhibitor, exhibit low toxicity to
bacteria and have less effects on bacterial colonization compared to G43. The in vivo study
athogens 2021, 10, x FOR PEER REVIEW 11 of 15
showed a marked reduction of dental caries in rats, representing a promising adjuvant to
athogens
thogens 2021, 10,, xx FOR
2021, 10 FOR PEER
PEER REVIEW
REVIEW 11 of
11 of 15
15
the control of dental caries [113].
Table 4. Small molecules designed by target-based approaches.
Table 4. Small molecules designed by target-based approaches.
Small Molecules TableChemical
Table 4. Small
4. Small molecules
molecules designed by
Formula designed by target-based
target-based approaches.
approaches.
Mechanisms References
Small Molecules Chemical Formula Mechanisms References
Small Molecules
Small Molecules Chemical Formula
Chemical Formula Mechanisms
Mechanisms References
References
Selectively bond
Selectively GtfC
bond andand
GtfC significantly inhibit
significantly thethe
inhibit
Compound IIIF1 IIIF1
Compound Selectively bond
Selectively bondbiofilm
GtfC
GtfC and
and significantly
significantly inhibit the
the [113] [113]
Compound III
Compound IIIF1F1 biofilm formation inhibit
formation [113]
[113]
biofilm formation
biofilm formation

Inhibit SrtA and reduce the adhesion and biofilm

Myricetin (Myr) Inhibit
Inhibit SrtA
SrtA
Inhibit and
and
SrtA reduce
reduce
and theS.the
the
reduce adhesion
adhesion andand
and
adhesion biofilm
biofilm
biofilm [106]
Myricetin
Myricetin (Myr)(Myr)
(Myr)
Myricetin formation of mutans [106]
[106] [106]
formation of S.
formation
formation of S. mutans
S. mutans
ofmutans

Inhibit the adhesion and biofilm formation of S.

Peptide (p1025) Inhibit the
Inhibit the adhesion
adhesion and
and biofilm
biofilm formation
formation of S. [107,108,109]
of S.
Peptide
Peptide (p1025)
Peptide (p1025)
(p1025) mutans
Inhibit the adhesion and [107,108,109]
biofilm formation of S. mutans [107–109]
[107,108,109]
mutans
mutans

9b Inhibit S.mutans biofilms by inhibiting Gtfs [112]

9b
9b 9b Inhibit S.mutans
Inhibit
Inhibit S.mutans biofilms
S.mutans by inhibiting
biofilms
biofilms by inhibiting GtfsGtfs
by inhibiting
Gtfs [112]
[112] [112]

6. Conclusions
6. Conclusions
6. Conclusions
S. mutans is a well-recognized cariogenic species in the oral cavity. The effective
6. Conclusions
S. mutans
S.
inhibition mutans is aa well-recognized
is
or removal well-recognized
of this cariogenic cariogenic
cariogenic
bacterium species
species in the
in
is essential thefor oral
oralthe cavity.
cavity.
caries The effective
The effective
management.
inhibition
inhibition or
or S. mutans
removal
removal of
of is acariogenic
this
this well-recognized
cariogenic bacterium
bacterium cariogenic
is
is essential
essentialspeciesfor
for in caries
the
the the
caries oral cavity. The effective
management.
management.
Small molecules
inhibition are or
promising
removalin in this
ofthis field
thisfield
cariogenicdue tobacterium
their goodisantimicrobial activity,
essential for activity,
the caries good
management.
Small
Small molecules
molecules
selectivity,Small are
are
and molecules promising
promising
low toxicity. in
Drugthis field due
due
repurposing, to
to their
their
drug good
good antimicrobial
antimicrobial
screening from activity,
either good
good
small-
selectivity,
selectivity, and low
and lowortoxicity.
toxicity.are promising
Drug
Drug in this fielddrug
repurposing,
repurposing, due to
drug their good
screening
screening from
fromantimicrobial
eitherpractical
either activity, good
small-
small-
molecule selectivity,
libraries and natural
low resources,
toxicity. Drug and target-based
repurposing, drug designing
screening from are either small-molecule
molecule
molecule
approaches libraries
libraries or natural
or
to the development natural resources,
resources,
of smalland and target-based
and
molecules target-based
that can designing
designing
effectively are S.
are
inhibit practical
practical
mutans
approaches libraries
to the or natural resources,
development of small target-based
molecules that designing
can effectivelyare practical
inhibit S.approaches
mutans to the
approaches
and consequently to the development
benefit caries of small
control. molecules
However, that
many can effectively
issues have inhibit
yet to S.
be mutans
solved.
and development
consequently of
benefit the small molecules
caries control.
control. that
However, can effectively
many inhibit
issues have S. mutans
have evaluation
yet toto be and
be solved.
solved.consequently
and
First,consequently
the benefit
cytotoxicity benefit caries However, many issues yet
caries of control.novel However, moleculesmany issues needs comprehensive
have yet to be solved. First, the before
cytotoxicity of
First,
First, the
the cytotoxicity
cytotoxicity
clinical translation, of
of the
the
particularly novel
novel molecules
molecules
for comprehensive needs
needs
the synthetic molecules. comprehensive
comprehensive evaluation
evaluation before
before
the novel molecules needs evaluationAlthough before clinical drugtranslation,
repurposing particularly
clinical
clinical translation,
translation,
has advantages particularly
particularly for the
for the synthetic
synthetic molecules.
molecules. Although
Although drug
drug repurposing
repurposing
for thesuch as lower
synthetic cost,
molecules. shorter
Although development
drug repurposingtimelines, hasand relatively
advantages higher
such as lower cost,
has
has advantages
advantages
safety, how such as
such
to reduce asitslower
lower known cost,side
cost, shorter
shorter effects development
development
and adverse timelines,
timelines,
reactions andstill
and relatively
relatively
needs higher
higher
further
shorter development timelines, and relatively higher safety, how to reduce its known side
safety,
safety, how
how
exploration. to
to
In reduce
reduce
addition, its
itsthe known
known
applicationside
side effects
effects
of reused and
and adverse
adverse
drug is reactions
reactions
limited because still
still of needs
needs
their further
further
original
effects and adverse reactions still needs further exploration. In addition, the application
exploration.
exploration.
effects, and In addition,
In addition, the application
the application of reused
of reused drug is
drug is limited because
limited because of their
of their original
original
of thereused indication
drug isof reusedbecause
limited drugs is
of narrow compared
their original to antibiotics.
effects, and the indication Second, of reused
effects,
effects, and
and
although the the
themode indication
indication
of actions of
of reused
reused
such astothe drugs
drugs is
is narrow
narrow
inhibitionSecond, compared
compared
of Gtfs and to
to antibiotics.
antibiotics.
the suppression Second,
Second,
drugs is narrow compared antibiotics. although the mode ofofactions acid such as
although
although
production thehave
the mode
mode beenof actions
of actions such
demonstrated such as asforthe
themany inhibition
inhibition
smallof of Gtfs
of Gtfs and
molecules, andthe the
the suppression
suppression
underlying of acid
of
molecular acid
the inhibition of Gtfs and the suppression acid production have been demonstrated for
production
production
mechanisms have
have been demonstrated
been
of these demonstrated areforfor many
many smallThird,
small molecules, the
molecules, the underlying
oralunderlying molecular
molecular
many smallcompounds
molecules, the still not clear.
underlying molecular since mechanisms biofilms
of these consisted
compounds of are still
mechanisms
mechanisms
numerousnot of
of these
these
microorganisms, compounds
compounds how are
are still
still not
not clear.
clear. Third,
Third, since
since oral
oral biofilms
biofilms consisted
consisted of
of
clear. Third, since oral to increase
biofilms the selectivity
consisted of numerous of microorganisms,
small moleculeshow that to increase
numerous
numerous microorganisms,
microorganisms, how to
how to increase with
increase the selectivity
the selectivity offlora
of small molecules that
specifically the target S. mutans
selectivity of smallwithout interfering
molecules other
that specifically normal
target S.small
mutans molecules
is one of the future
without that
interfering with
specifically
specifically
directionsother target
target
for normal S.
S. mutans
mutans
drug development. without
without
flora is one of the interfering
interfering
Specific with
with
futureinhibitors other
other
directions for normal
normal
against flora
flora is
is one
one
S. mutans still
drug development. of
of the
the future
future
need inhibitors
Specific
directions
directions
comprehensive for drug
for
against drug development.
development.
S. mutans
validation instill
complex Specific
needSpecific
comprehensive
microbial inhibitors
inhibitors against
against
validation
consortia. Finally, S. the
S.
in mutans
mutans
complex still need
still need
microbial
development of consortia.
comprehensive
comprehensive Finally,
drug resistance validation
validation
by the
oraldevelopment
bacteriain complex
in complex ofadrug
is still microbial
microbial
concern consortia.
consortia.
resistance
that by oral
needs Finally,
a Finally,
bacteria
long-term theevaluation
the development
isdevelopment
still a concern
in both ofthat needs
of
drug
drug resistance
resistance
in vitro a long-term
and by
inby oralmodels.
oral
vivo bacteriaNevertheless,
bacteria
evaluation is still
is still aa concern
in both concern
in vitro that
that
and needs
needs
antimicrobial in vivo aa small
long-term
long-term
models. evaluation
evaluation
moleculesNevertheless, in both
in
represent both
antimicrobial
a
in
in vitro
vitro and
and
promisingsmall in
in
approach vivo
vivo
molecules models.
models.
to the Nevertheless,
Nevertheless,
represent
effectivea promising
inhibitionantimicrobial
antimicrobial
approach
of S. to small
small molecules
molecules
the effective
mutans and will represent
represent
inhibition
benefit of S. a
amutans
the and
promising
promising willapproach
approach
benefit
management of dental caries. to
to
the the
the effective
effective
management ofinhibition
inhibition
dental of
of
caries. S.
S. mutans
mutans and
and will
will benefit
benefit the
the
management of
management of dental
dental caries.
caries.
Author Contributions:
Author Contributions: S.Y. and J.Z.S.Y.conceptualized
and J.Z. conceptualized the manuscript.
the manuscript. S.Y. createdS.Y.thecreated
figuresthe
andfigures and
Author
Author
wrote theContributions:
Contributions: S.Y. and
S.Y. and
wrote the manuscript.
manuscript. R.Y. J.Z.
J.Z.
edited conceptualized
conceptualized
R.Y.
the edited the manuscript.
the manuscript.
the manuscript.
manuscript. X.X. editedX.X. S.Y.
S.Y.
and edited
wrote created
created
and the
the
somewrote figures
figures
some
sections and
ofand
sections
the of the
wrote
wrote the manuscript.
the
manuscript. manuscript.
manuscript. R.Y.
All authorsR.Y.
All edited
edited
authors
have theagreed
the
have
read and manuscript.
manuscript.
read and X.X.to
X.X.
agreed
to the edited
edited and wrote
and
the version
published wrote
published some
some
version
of the sections
ofsections of the
of the
the manuscript.
manuscript.
manuscript. All
manuscript. All authors
authors have
have read
read and
and agreed
agreed to
to the
the published
published version
version of
of the
the manuscript.
manuscript.
Funding: This study was supported by the National Natural Science Foundation of China (81771099
Funding:
Funding: This study
This
and 81800989). study was
was supported
supported by by the
the National
National Natural
Natural Science
Science Foundation
Foundation of of China
China (81771099
(81771099
and 81800989).
and 81800989).
Institutional Review Board Statement: Not applicable.
Institutional Review
Institutional Review Board
Board Statement:
Statement: NotNot applicable.
applicable.
Pathogens 2021, 10, 1540 12 of 16

Funding: This study was supported by the National Natural Science Foundation of China (81771099
and 81800989).
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Conflicts of Interest: The author declare no conflict of interest.

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