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Acne vulgaris: new evidence in pathogenesis and

future modalities of treatment

Neirita Hazarika

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JOURNAL OF DERMATOLOGICAL TREATMENT
https://doi.org/10.1080/09546634.2019.1654075

REVIEW ARTICLE

Acne vulgaris: new evidence in pathogenesis and future modalities of treatment

Neirita Hazarika
Department of Dermatology, All India Institute of Medical Sciences, Rishikesh, India

ABSTRACT ARTICLE HISTORY

Acne vulgaris, a common and chronic disorder of the pilosebaceous unit, affects up to 85% of adolescent Received 12 June 2019
and young adults. While a lot is already known about acne and its treatment, still the gaps in our under- Accepted 2 August 2019
standing of acne remains. This article will review the emerging evidence in the complex pathogenesis of
KEYWORDS
acne and provide an overview of the potential future therapy in management of acne vulgaris.
Acne vulgaris;
Propionibacterium acnes;
KEY POINTS
biofilm; diet; future therapy

What is known? Propionibacterium acnes targeted therapy has been the mainstay in the manage-
ment of acne till now.

What is new? Sebocyte activity is controlled via a range of cellular pathways and hormones in add-
ition to androgens. This has opened an array of therapeutic options to be available for treating acne
in the near future.

Introduction Emerging evidence in pathogenesis

According to the Global Burden of Disease (GBD) study, acne vul-
garis affects 85% of young adults’ aged 12–25 years (1). The
pathogenesis of acne is multifactorial. Traditionally, four distinct
processes were believed to play critical roles: increased sebum
production, alteration of keratinization processes leading to come-
done formation, follicular colonization by Propionibacterium acnes
(P. acnes) and inflammatory mediators around pilosebaceous unit
(PSU). The main objective of this review is to highlight the emerg-
ing evidence in the complex pathogenesis of acne vulgaris and
provide an overview of the novel molecules being evaluated for
treatment of acne, with a short focus into relevant pathogenic
pathways in relation to mechanisms of action of these
novel therapies.
Methods
Literature searches were conducted in PubMed and National
Institutes of Health ongoing trials register (www.clinicaltrials.gov)
in April 2019 using both Medical Subject Headings (MESH) terms
and search phrases: ‘acne vulgaris’, ‘acne vulgaris pathogenesis’,
‘Propionibacterium acnes’, ‘acne vulgaris diet’, ‘acne vulgaris bio-
film’, and ‘acne vulgaris treatment’. The search was limited to all
articles in English, published since 2008. Bibliography of included
publications was manually searched for additional studies. Few
publications prior to 2008, relevant to this review, were also
included. Only ongoing trials involving new molecules as drugs,
not commercially available for use, were included. Trials with
medical devices and trials on acne scarring were excluded, as
they were beyond the scope of this review. This review used data
that are publicly available and is not primary research; therefore,
approval by an institutional review board is not required.
Current research on genome-wide associations with severe acne
has identified six gene loci: 11q13.1, 5q11.2, 11p11.2, 1q41,
1q24.2, and 8q24. These loci are involved in androgen metabol-
ism, inflammation processes, and scar formation (2–4). A marked
increase of tumor necrosis factor (TNF) gene transcripts was
observed in acne lesions (5). Also, a meta-analysis suggests that
the –308G/A polymorphism in the TNF gene contributes to acne
risk in Caucasians (6). Insulin-like growth factor 1 (IGF-1) poly-
morphism also has recently been shown to predispose Turkish
individuals to acne (7).
There has been recent focus on the epidermal permeability
barrier and sebum, of untreated skin of people with acne. Within
acne lesions, there is an increase in filaggrin expression in follicu-
lar keratinocytes. P. acnes has been shown to increase filaggrin
expression in cultured keratinocytes. The hypothesis proposed is
that, a reduced ability to express filaggrin due to null mutation
in the filaggrin gene, correlates directly with a lesser ability to
form acne lesions (8). There is need for more studies to
validate this hypothesis. Acne patients were shown to have sig-
nificantly reduced free sphingosine and total ceramides in their
stratum corneum, which correlates with impairment of the stra-
tum corneum permeability barrier (9). In males with acne, the
sebum quantity was 59-percent higher, squalene was increased
approximately twofold, and free fatty acids were decreased (10).
Also, acne-prone individuals have a higher amount of lobules per
sebaceous gland and the overall size of the follicles is
increased (11).
Recent work suggests that the formation of sebocytes is regu-
lated by several molecular pathways (e.g. Lef-1, Blimp1, Wnt,
C-myc) and that sebocyte activity is controlled via a range of cel-
lular pathways and hormones in addition to androgens including,
for example, peroxisome proliferator-activated receptors, sub-
stance P receptors, a-melanocyte-stimulating hormone (a-MSH),

CONTACT Neirita Hazarika neiritahazarika@yahoo.com Department of Dermatology, All India Institute of Medical Sciences, Rishikesh, India
ß 2019 Taylor & Francis Group, LLC
2 N. HAZARIKA
insulin-like growth factor, corticotropin-releasing hormone, vita-
min D (VD), and ectopeptidases (11).
The role of IGF-1 in the pathogenesis of acne has been exten-
sively studied. Deplewski and Rosenfield pointed out that not
serum androgens but serum IGF-1 levels correlate with the clinical
manifestation of acne (12). IGF-1 is a potent inducer of gonadal
testosterone and adrenal dehydroepiandrosterone (DHEA) synthe-
sis and also, promotes the intracutaneous conversion of testoster-
one to dihydrotestosterone (DHT) by enhancing 5a-reductase
activity (13). Androgen receptor (AR) activation requires two major
stimuli: (1) binding of its hormone ligand (androgen) and (2)
depression of its inhibitory nuclear coregulator Forkhead box pro-
tein O1 (FoxO1). Ligand-mediated activation of AR depends on
androgen binding affinity, highest exhibited by DHT, which is 10
times higher than testosterone. Once converted, DHT has the cap-
ability of activating its intranuclear receptor AR, regulated by
FoxO1. FoxO1 in turn is inhibited by the protein kinase Akt, a
downstream target associated with insulin- and IGF-1-receptor
activation. Therefore, transient rises of insulin and IGF-1 occurring
during the normal course of puberty inhibit FoxO1 regulation and
allow the activated AR to trigger a chain of metabolic events,
which lead to an excess production of keratinocytes and sebum
(14). The proliferating ductal lining cells unable to escape the
infundibulum of the PSU form a plug, compromise the availability
of diffusible oxygen to cells below, providing an ideal, anoxic
environment for P. acnes to grow.
P. acnes and biofilm formation
The role of P. acnes in the pathogenesis of acne, however,
remains controversial. Conflicting opinions arise from the fact that
P. acnes is a dominant member of the normal cutaneous flora,
while few studies have shown that it induces inflammatory
responses in skin parenchymal cells and immune cells. Utilizing
more refined DNA-based typing methods, recently it was found
that P. acnes consists of phylogenetically distinct cluster groups
with various pathogenic characteristics, including differing abilities
to elicit inflammation and differing secretome profiles. This evi-
dence may suggest that while some P. acnes strains may play an
etiological role in acne, others are associated with health (15).
Jahns et al. demonstrated extensive P. acnes biofilms in the
sebaceous follicles of patients with acne. They did not find any
qualitative differences between P. acnes biofilms in acne and con-
trols, indicating that phenotypic, rather than genetic, changes
associated with biofilm formation may account for the pathogenic
role of P. acnes (16). Biofilm formation substantially increases
P. acnes virulence, associated with enhanced expression of
exogenous P. acnes triglyceride lipase that increases sebum con-
centrations of free palmitate and oleate. Free oleic acid increases
P. acnes adherence and growth (13). Abundance of sebum-derived
free palmitate together with P. acnes-derived danger-associated
molecular patterns (DAMPs) stimulates innate immunity, inflam-
masome activation in neutrophils, and interleukin-1b (IL-1b)-sig-
naling. IL-1b finally orchestrates follicular and perifollicular
inflammation with Th17 cell differentiation and IL-17-mediated
local keratinocyte hyperproliferation (13). P. acnes also induces fol-
licular keratinocytes to release IL-1a leading to keratinocyte prolif-
eration and comedone formation (17). Pawin et al. have proposed
that P. acnes itself may act as a superantigen, activating cells to
proliferate and to accumulate (18). P. acnes also induces the
expression of TLR-2 on keratinocytes and the secretion of pro-
inflammatory cytokines and matrix metalloproteinase-9 (MMP-9)
(19). MMP-9 enhances follicular rupture, as does invasion of CD4
cells, which further spreads inflammation through the dermis (20).
Furthermore, P. acnes release chemotactic factors, which first
recruit CD4-lymphocytes, and later neutrophils and monocytes to
the affected area. Activation of Toll-like receptor 2 (TLR-2) on
monocytes by P. acnes induces the production of interleukin (IL)-8
which subsequently leads to the recruitment of neutrophils into
the PSU (21,22). P. acnes also interacts with antimicrobial peptides
(AMPs) and protease-activated receptors (20). One of the most
important aspect of P. acnes biofilm is that it acts as a protective
physical barrier, limiting effective anti-microbial concentrations
within the biofilm. It further promotes antibiotic resistance of the
colonies by production of certain proteins (23).
Diet and acne
High glycemic index foods, including glucose, white bread, white
rice, and chocolate, stimulate the release of insulin which then
activates the Akt signaling pathway directly through its receptor
and indirectly through the production of IGF-1 and its receptor.
The protein kinase Akt then phosphorylates FoxO1, and inacti-
vates it. FoxO1 deactivation in turn leads to gene transcription
that drives the proliferation of keratinocytes in the PSU (14).
The protein, mechanistic target of rapamycin complex 1
(mTORC1), controls lipogenesis and protein synthesis that drive
sebaceous activity and ductal plugging, respectively. mTORC1 has
recently been recognized to play a major role in diet-induced
acne. Insulin, IGF-1, essential branched-chain amino acid leucine
(found in dairy milk and whey, meat and egg), and glutamine,
cause full activation of mTORC1 signaling. On the other hand,
FoxO1 and FoxO3 are negative regulators of the nutrient-sensitive
kinase mTORC1. Cow milk is also known to contain anabolic
androgen precursors of DHT, including 5a-pregnanedoine, 5a-
pregnan-3B-ol-20-one, 5a-androstene-3B, 17B-diol, 5a-androstane-
doin, and 5a-androstan-3B-ol-17-one (14).
Adiponectin is an adipocyte-derived hormone that inhibits
proinflammatory cytokines and induces anti-inflammatory ones,
down-regulates adhesion molecule expression, suppresses toll-like
receptors and their ligands, and increases insulin sensitivity. It
inhibits mTORC1 activity by activating 50 adenosine monophos-
phate (AMP)-activated protein kinase. Dietary glycemic index and
glycemic load have been shown to be inversely associated with
adiponectin concentrations. Hypoadiponectinemia associated with
a high-glycemic-index/-load diet may augment the inflammatory
response in patients with acne. In a study done on 50 acne
patients and 36 healthy controls, glycemic index and glycemic
load levels were significantly higher (p ¼ 0.022 and p¼.001,
respectively) and serum adiponectin levels were significantly
lower (p¼.015) in patients with acne than in controls. There was
an inverse correlation between serum adiponectin concentration
and glycemic index (p¼.049, r ¼ 0.212). Also, the glycemic index
values were significantly higher in patients with moderate and
severe acne than in patients with mild acne, and positively corre-
lated with disease severity (24).
A look into the future in acne management
New knowledge into the complex pathogenesis of acne have
opened an array of possibilities for new treatment targets. Due to
the growing concern over bacterial resistance, antibiotic use in
treatment of acne will decline over the next years and will be
substituted with AMPs, bacteriophages, agents decreasing sebum,

monoclonal antibodies, and various novel pharmacological agents
including vaccines against P. acnes.
Agents decreasing sebum production (Table 1)
Via action on androgen-dependent sebum production pathway
Clinical trial on topical cortexolone 17a-propionate 1% cream or
CB-03-01, a synthetic, steroidal antiandrogen, which acts by inhib-
iting the interaction of circulating androgens with their receptor
is underway (NCT02682264) (25). Use of topical ASC-J9 cream in
acne, a synthetic AR degradation enhancer, has also been eval-
uated (NCT00525499) (26). NVN1000 gel or SB204, releases nitric
oxide (NO) when applied topically and inhibits the androgen-
dependent sebum production pathway (27). Safety of use of
NVN1000 gel in acne has been evaluated in trial (NCT01844752)
(28). Epigallocatechin-3-gallate (EGCG), a major polyphenolic con-
stituent in green tea, inhibits 5a-reductase-1 activity (29). It also
inhibits cell proliferation and lipid synthesis in sebocytes in vitro
via inhibiting IGF-1 mediated androgen-induced lipogenesis (30).
A study on the use of EGCG in acne was undertaken
(NCT01687556) (31).
Via action on a-melanocyte-stimulating hormone
Alpha-melanocyte-stimulating hormone causes increased sebo-
genesis in rodents via the stimulation of the melanocortin recep-
tor 1 (MC1-R) and the melanocortin receptor 5 (MC5-R), also
expressed in human sebocytes. JNJ 10229570, an MC1-R and
MC5-R antagonist, decreases sebaceous gland’s size and produc-
tion of sebaceous lipids in cultured primary human sebocytes
(32). and its use has been evaluated in a trial (NCT01492647) (33).
Peroxisome proliferator activated receptor (PPAR) modulators
PPARs are ligand-activated transcription factors that upregulate
lipid synthesis. Certain leukotrienes are potent PPAR ligands, such
as leukotriene B4 (LTB4). LTB4 is considered to be a major player
in the development of tissue inflammation. Synthesis of LTB4 is
controlled by the enzyme 5-lipoxygenase (5-LOX). Zileuton, an
oral 5-LOX inhibitor that downregulates expression of LTB4 in
sebaceous gland and inhibits PPAR-mediated lipogenesis (34),
underwent a clinical trial for safety and efficacy in acne
(NCT00098358) (35). The results of a phase 2 study (2016-000540-
33), with the PPAR-c modulator, N-acetyl-GED-0507-34-LEVO, in
1% and 2% gel in acne are awaited (36). Acebilustat (CTX-4430), a
leukotriene A4 hydrolase inhibitor, is also under investigation
(NCT02385760) in patients with moderate to severe acne (37).
Acetylcholine (Ach) inhibitors
Ach increases lipid synthesis by its interaction with the Ach recep-
tor a7, expressed in sebaceous glands (38). Botulinum toxin inhib-
its the presynaptic release of Ach and has recently been found to
noticeably decrease sebum production, oily skin, and pore size
(39). A topical formulation of botulinum toxin was tested in trial
(NCT01293552) (40).
Acetyl coenzyme a carboxylase inhibitors
Androgenic stimulation of sebaceous glands increases key
enzymes involved in the regulatory steps of sebaceous fatty acid
biosynthesis, such as acetyl coenzyme A carboxylase (ACC) (32).
Topical DRM01B, an inhibitor of enzyme ACC, is under trial
(NCT03127956) (41).
JOURNAL OF DERMATOLOGICAL TREATMENT 3
Lupeol
Lupeol is an alcoholic, pentacyclic triterpene, obtained from the
hexane extract of Solanum melongena L., a medicinal plant from
Solanum species. Lupeol strongly suppressed lipogenesis by mod-
ulating the ‘IGF-1R/phosphatidylinositide 3 kinase/Akt/sterol
response element-binding protein-1 (SREBP-1)’ signaling pathway
in SEB-1 sebocytes, and reduced inflammation by suppressing the
NF-jB pathway in SEB-1 sebocytes and HaCaT keratinocytes (42).
5a-reductase inhibitors
Finasteride has preferential selectivity for enzyme 5a-reductase
type 2. A clinical trial (NCT02502669) was undertaken to evaluate
the efficacy and safety of once weekly, high-dose oral finasteride
(23.5 and 33.5 mg) for the treatment of severe nodulocystic acne
in males (43). However, there is no rationale for use of finasteride
in female patients with acne.
Agents that primarily normalize abnormal keratinization within
PSU (Table 2)
Talarozole (Rambazole/R115866)
It is a selective azole derivative that inhibits the CYP26 isoenzyme,
involved in the metabolism of retinoic acid (RA). By inhibiting
CYP26, it enhances the intracellular endogenous levels of all-
trans-RA, allowing for normalization of desquamation of the epi-
thelium, and thus may decrease comedone formation in acne
(44). In a study by Verfaille et al., oral R115866 1 mg once daily
for 12 weeks in patients with moderate to severe facial acne vul-
garis was shown to be efficacious and well tolerated (45).
Monoclonal antibody against interleukin 1a (IL-1a)
P. acnes activate the release of IL-1a via Toll like recepter-2 activa-
tion. In vitro models of acne have determined that stimulation of
the pilosebaceous infundibulum with IL-1a induces a hyperkerati-
nization response similar to that seen in comedones (46). RA-18C3
is a human monoclonal antibody specific for IL-1a. A phase 2 trial
of RA-18C3 in moderate to severe acne vulgaris (NCT01474798), is
under way (47).
Agents acting on P. acnes (Table 3)
Newer antibiotics
Pentobra: Tobramycin is conjugated to a short 12AA peptide to
form composite molecule, Pentobra. Pentobra combines the
potent ribosomal activity of aminoglycosides with the bacteria-
selective membrane-permeabilizing abilities of AMPs and demon-
strated potent and selective killing of P. acnes along with suppres-
sion of some P. acnes-induced chemokines (48).
Sarecycline is a new, once-daily, tetracycline-class antibiotic. In
a multicenter, phase 2, dose-ranging study (NCT02320149), the
efficacy and safety of oral sarecycline as once-daily, narrow spec-
trum antibiotic for the treatment of moderate to severe facial
acne vulgaris was evaluated with satisfactory results (49).
Zolav# is a p-carboethoxy-tristyrylbenzene derivative that
interacts with novel mechanosensitive ion channel of large con-
ductance (MscL) and inhibits bacterial growth (50). At a final con-
centration of 50 mg/mL, Zolav# is effective in reducing the P.
acnes burden in a mouse intradermal infection model (51).
NAI: Bacterial elongation factor Tu (EF-Tu) and EF-Ts are inter-
acting proteins involved in polypeptide chain elongation in pro-
tein biosynthesis (52). NAI, a semi-synthetic thiopeptide, is a
peptide EF-Tu inhibitor, and highly selective against P. acnes, and
4 N. HAZARIKA

Table 1. Future of acne therapy – agents that decrease sebum production.

Study
Name of drug started Purpose of study Study design Result
Via action on androgen-dependent sebum production pathway
CB-03-01/ 2016 To determine the long-term safety of CB- Multicenter, open label, long- Ongoing study
Cortexolone 03-01 cream, 1%, applied twice daily for term extension study
17a propionate an additional nine months in study (NCT02682264)
participants with acne vulgaris that
participated in the Phase 3 pivotal studies
for a total treatment of up to 12 months.
ASC-J9 2007 To evaluate the safety and efficacy of two Phase 2, multi-center, ASC-J9 cream (0.001% vs. 0.005
different concentrations of ASC-J9 cream randomized, double-blind, vs. 0.025%) in changing the
(0.1 and 0.025%) applied topically twice vehicle-controlled dose-ranging percentage of inflammatory
daily for 12 weeks clinical study (NCT00525499) lesion counts –34.7 vs. –30.7 vs.
–44.8 SD
Improvement in Investigator
Global Assessment by at least
one grade (0.001% vs. 0.005vs.
0.025% ASC-J9) in 20 vs. 23 vs.
28 participants
NVN1000 2013 To compare the efficacy, tolerability and Phase 2/3, multi center, Both 1% and 4% NVN1000 gel
safety of NVN1000 gel 1% and 4% with randomized, double-blinded, significantly decreased
vehicle gel twice vehicle-controlled, parallel- noninflammatory lesions; 4%
daily group, three-arm study NVN1000 gel also significantly
(NCT01844752) decreased the
inflammatory lesions
Epigallocatechin-3- 2012 To determine the clinical and histological Phase 1, randomized, double- No official results have been
gallate (EGCG) effects of 1% and 5% EGCG solution blind, vehicle-controlled study posted in ClinicalTrials.gov
applied topically to the face twice a day (NCT01687556)
for 8 weeks
Via action on a-melanocyte-stimulating hormone (a-MSH)
JNJ 10229570 2011 A study of JNJ 10229570-AAA to evaluate Phase 2, multi center, double- No official results have been
safety and tolerability in Japanese blind, vehicle-controlled study posted in ClinicalTrials.gov
participants with acne vulgaris (NCT01492647)
Peroxisome proliferator activated receptor (PPAR) modulators
Zileuton 2004 To test the safety and efficacy of oral Phase 2, randomized, double- No official results have been
5-lipoxygenase (5-LOX) zileuton in the treatment of facial acne blind, placebo-controlled, posted in ClinicalTrials.gov
inhibitor parallel-group, multicenter
study (NCT00098358)
N-Acetyl-GED- 2016 To evaluate the efficacy and safety of N- Phase 2, double-blind, No official results have been
0507–34-LEVO acetyl-GED-0507-34-LEVO gel, 1 and 2%, randomized, placebo-controlled posted in ClinicalTrials.gov
applied once daily for 12 weeks in clinical study (2016-000540-33)
patients with mild acne.
Acebilustat (CTX-4430) 2015 To study the efficacy and safety study of Phase 2, multi-center, double- No official results have been
leukotriene A4 oral CTX-4430, 100 mg, once-daily for 12 blind, randomized, parallel posted in ClinicalTrials.gov
hydrolase inhibitor weeks for the treatment of moderate to group (NCT02385760)
severe facial acne vulgaris.
Acetylcholine (ACH) inhibitors
ANT-1207 (topical 2012 To determine the safety, tolerance and Phase 2, randomized, double- No official results have been
formulation of efficacy of ANT-1207 blind, vehicle-controlled study posted in ClinicalTrials.gov
botulinum toxin) (NCT01293552)
Acetyl coenzyme A carboxylase (ACC) inhibitors
DRM01B/ 2017 To assess the long-term safety of Phase 3, randomized, double- Ongoing
Olumacostat Glasaretil Olumacostat Glasaretil gel, 5.0% in blind, vehicle controlled,
patients with acne vulgaris efficacy and safety study
(NCT03127956)
IGF-1R/phosphatidylinositide 3 kinase/Akt/sterol response element-binding protein-1 (SREBP-1) signaling pathway modulator
Lupeol 2015 To explore alternative acne medications, Experimental (in vitro and in Lupeol attenuated the
skin specimens including typical acne vivo study) manifestation of infiltrated
lesions were acquired from patients inflammatory cells around
before and after applying 2% lupeol comedones or sebaceous glands.
twice daily for 4 weeks. Also, it significantly decreased
expressions of IGF-1R, SREBP-1,
NF-kB p65, and IL-8 in the
human acne lesion
5a-reductase inhibitors
Finasteride 2015 To evaluate the efficacy and safety of Phase 2, double-blind, No official results have been
once weekly, high-dose oral finasteride randomized, placebo- posted in ClinicalTrials.gov
(23.5 and 33.5 mg) compared to placebo controlled, dose-ranging study
for the treatment of severe nodulocystic (NCT02502669)
acne in male subjects
 JOURNAL OF DERMATOLOGICAL TREATMENT 5

Table 2. Future of acne therapy – agents that primarily normalize abnormal keratinization within the PSU.
Name of drug
Talarozole (Rambazole/R115866)
Monoclonal antibody against
interleukin 1a (IL-1a)
RA-18C3
Study year Purpose of study
2005 To assess the safety and efficacy
of 1 mg oral talarozole taken
once daily for 12 weeks in the
treatment of moderate-to-severe
facial acne
2011 To assess the safety,
pharmacokinetics, and efficacy
of a true human anti-
inflammatory therapeutic
antibody (RA-18C3) in subjects
with moderate to severe
acne vulgaris
Study design Result
Exploratory trial A mean reduction in
inflammatory lesion count of
77.4% (p<.001), in
noninflammatory lesion count of
58.3% (p<.001) and in total
lesion count of 76.0% (p<.001)
was observed as compared
with baseline.
Phase 2, open label study No official results have been
(NCT01474798) posted in ClinicalTrials.gov

is currently under evaluation as a 3% gel for acne (2014-001491- 12 weeks, in the treatment of acne vulgaris has been evaluated
62) (36). (NCT00714454)(58).

Agents acting on P. acnes biofilm

Rifampicin alone and in combination, against planktonic and bio-
film of P. acnes was evaluated by Tafin et al., in an in vitro and in
a foreign-body infection model (53). Rifampicin may be used in
the future as an anti-acne agent.
Next Science Acne Gel (NAG) is a topical gel containing sali-
cylic acid which causes biofilm matrix degradation. Extracellular
polysaccharide (EPS) polymers encapsulate bio-films, protecting P.
acnes from conventional treatments. NAG contains a chelating
agent and buffer which remove ionic bonds between the EPS to
disrupt the network. Also, it contains isopropyl alcohol and surfac-
tant which solubilize EPS, allowing salicylic acid to effectively
reach P. acnes. As the EPS is removed, the minimum monograph
concentration of salicylic acid (0.5%) in NAG is highly effective,
with very low tissue toxicity or irritation as shown in trail
(NCT02404285) (54).
Vaccines against P. acnes
It has not been clearly shown that vaccines against P. acnes anti-
genic structures are effective in humans with acne. In sebocytes
treated with the antiserum from mice immunized with the heat
inactivated P. acnes vaccine, the percentage of cytotoxicity and
level of IL-8 were significantly reduced. However, it did not affect
the survival/growth rate of P. acnes (59).
P. acnes surface enzyme sialidase plays a significant role in the
adhesion of P. acnes to host cells (required for P. acnes coloniza-
tion of sebaceous glands). Anti-serum from mice vaccinated with
recombinant P. acnes sialidase was shown to decrease P. acnes-
induced human sebocyte cytotoxicity, IL-8 production and macro-
phage-inflammatory protein-2. As with the inactivated P. acnes
vaccine, the sialidase-component vaccine did not affect the sur-
vival/growth rate of P. acnes (59).

Antimicrobial peptides
MBI 226 or omiganan pentahydrochloride, is a topical cationic
peptide derived from bovine AMP indolicidin. MBI 226 has rapid
in vitro microbicidal activity against a variety of bacteria by dis-
rupting their cytoplasmic membranes and causing depolarization
followed by cell death (32). The safety and efficacy of MBI 226
2.5% and 5.0% solutions in the treatment of acne vulgaris are
being evaluated (NCT00211523) (55).
Tyrothricin, produced by Bacillus brevis, is a polypeptide anti-
biotic substance consisting of two cyclic decapeptides, gramicidin
S (22%) and tyrocidine A (78%). Both peptides have broad bacteri-
cidal activity against Gram-positive bacteria due to intercalation
of the peptides into bacterial membranes. The efficacy and toler-
ability of topical tyrothricin 0.1% in acne are being evaluated
(2013-001716-30) (56).
Agents decreasing inflammation around PSU (Table 4)
Nitric oxide-releasing nanoparticle (NO-np)
P. acnes causing induction of IL-1 cytokines through the NLRP3
inflammasome has been recently highlighted as a dominant etio-
logical factor for acne vulgaris. Nitric oxide, a potent biological
messenger has broad-spectrum antimicrobial and immunomodu-
latory properties. Qin et al. utilized an established nanotechnology
capable of generating/releasing NO over time (NO-np). P. acnes
was found to be highly sensitive to all concentrations of NO-np.
NO-np also significantly suppressed IL-1b, TNF-a, IL-8, and IL-6
from human monocytes and IL-8 and IL-6 from human keratino-
cytes (60).

Bacteriophages Phosphodiesterase inhibitors (PDEs inhibitors): Apremilast

Ten phage capable of lysing P. acnes were isolated from human
skin microflora and formulated into cetomacrogol cream aqueous
at a concentration of 2.5  108 PFU per gram and is being eval-
uated as a future anti-acne product (57).
Antioxidants
Vitamin C has shown action against P. acnes and prevents ultra-
violet A (UVA)-induced sebum oxidation (32). The efficacy and
safety of twice-daily sodium L-ascorbyl-2-phosphate 5% lotion, for
PDE inhibitors degrade intracytoplasmic levels of cAMP. Low lev-
els of cAMP lead to preferential expression of proinflammatory
cytokines TNF-a, IL-1, IL-8, IL-12, and IL-23. Apremilast, an oral
PDE4 inhibitor, elevates cAMP levels and inhibits TNF-a and IL-8
and thus, could potentially play a role in acne treatment (32). A
clinical trial to determine the safety and efficacy of 20 mg apremi-
last in the treatment of moderate-to-severe acne was undertaken
(NCT01074502)but was later terminated due to lack of fund-
ing (61).
6 N. HAZARIKA

Table 3. Future of acne therapy – agents acting on P. acnes.

Name of drug Study year Purpose of study
Newer antibiotics
Pentobra 2015 To engineer a P. acnes antibiotic by
combining the potent ribosomal activity
of aminoglycosides with the bacteria-
selective membrane-permeabilizing
abilities of AMPs
Sarecycline 2014 To evaluate the efficacy and safety of
an approximate 1.5 mg/kg/day dose of
oral sarecycline compared to placebo in
the treatment of moderate to severe
facial acne vulgaris
Zolav# 2015 To investigate the effectiveness of
Zolav#, a novel antibiotic as a
treatment for acne vulgaris.
NAI 2014 Evaluation of the efficacy and safety of
a new gel, NAI-Acne gel 3% applied
twice-a-day for 12 weeks to patients
with facial acne vulgaris in comparison
with placebo.
Agents against P. acnes biofilm
Rifampicin 2011 To investigate the activity of rifampicin
alone and in combination with other
antimicrobials against P. acnes biofilm in
vitro and in a foreign-body guinea pig
infection model.
NAG 2015 To study the effect of topical NAG gel
vs. vehicle for 12 week in subjects with
mild to moderate facial acne.
Antimicrobial peptides
MBI 226 2005 To evaluate the safety and efficacy of
MBI 226 2.5% and 5.0% solutions
applied topically for 12 weeks
Tyrothricin 2013 To investigate the efficacy and
tolerability of topical tyrothricin 0.1% in
the treatment of mild to severe acne
vulgaris compared clindamycin to
clindamycin and BPO 5%.
Bacteriophages
P. acnes bacteriophage To isolate and characterize phage which Experimental (in vitro and in
as could lyse P. acnes and to formulate the vivo study)
Cetomacrogol cream phage into a delivery form for potential
application in topical treatment
Antioxidants
Vitamin C 2008 To determine the efficacy of a twice-
daily sodium L-ascorbyl-2-phosphate
(APS) 5% lotion for 12 weeks
Vaccines against P. acnes
Whole-inactivated 2008 To evaluate whether vaccination against Experimental (in vivo study)
P. acnes vaccine P. acnes suppressed P. acnes-induced
skin inflammation.
P. acnes sialidase- 2007 To develop a vaccine using P. acnes
based vaccine surface enzyme sialidase that suppress
P. acnes-induced inflammation and
pathogenesis
Study design
Experimental (in vitro study)
Phase 3
Randomized, multicenter, double-
blind, placebo-controlled study
(NCT02320149)
Experimental (in vitro and in
vivo study)
Randomized, double-blind, placebo- No official results have been posted in
controlled study (2014-001491-62) ClinicalTrials.gov
Experimental study (in vitro and in
vivo study)
A multi-site, double-blind, vehicle-
controlled study (NCT02404285)
Phase 2 randomized, vehicle-
controlled, double-blind,
multicenter clinical trial
(NCT00211523)
A randomized, active comparator-
controlled, exploratory, observer-
blind clinical study (2013-
001716-30)
Phase 2, randomized, double-blind,
placebo-controlled trial
(NCT00714454)
Experimental (in vivo study)
Result
Bactericidal activity against a wide range of
P. acnes clinical isolates. Effectively killed P.
acnes from human donors in micro
comedone sebum-rich environment. Safe,
nonirritating on various skin cells.
Results submitted
No official results have been posted in
ClinicalTrials.gov
A concentration of 50 mg/ml (q8h) elicited a
two log difference in colony forming unit/
gram between treatment and control group
Rifampicin demonstrated highest in vitro
activity against P. acnes biofilm as a single
agent. Rifampicin and daptomycin
combination was most active regimen
against experimental P. acnes biofilm
Decrease of inflammatory lesions by 44%
and non-inflammatory lesions by 32% after
12 weeks
No official results have been posted in
ClinicalTrials.gov
The mean differences in inflammatory lesion
counts from baseline were –12.3 in
clindamycin þ BPO , –10.2 in BPO 5%, and
–7.7 in tyrothricin.
Cetomacrogol cream was capable of killing P.
acnes, even after the formulation was stored
for up to 90 days
No official results have been posted in
ClinicalTrials.gov
Antibodies elicited by inactivated P. acnes
based vaccine attenuated IL-8 production in
human sebocytes. However, it did not affect
the survival/growth rate of P. acnes.
Antibodies against sialidase provoked in
vaccinated mice effectively suppressed the P.
acnes-induced inflammation and neutralized
the cytotoxicity of P. acnes to
human sebocytes

Inhibitor of a isoform of p38 mitogen-activated protein kinase
(p38 MAPK or p38): SCIO-469
P. acnes induced proinflammatory cytokine release, is mediated
by P. acnes-induced activation of p38 mitogen-activated protein
kinase (p38 MAPK or p38) in human keratinocytes. SCIO-469 is a
relatively selective inhibitor of a isoform of p38 MAPK. Topical
treatment of SCIO-469 inhibited the P. acnes-induced phospho-
p38 and cytokine secretion in human epidermal equivalents (62).
via activation by caspase-1 in neutrophils. Also, perifollicular inter-
action of P. acnes with macrophages induce secretion of IL-1b
(32) Gevokizumab, is a humanized monoclonal IgG2 antibody that
shows high affinity and specificity to IL-1b. Inhibition of IL-1b
increases IL-6 release, reduces TNF-a levels and decreases neutro-
phil migration, thus reducing acute inflammation in vivo (63). The
potential use of gevokizumab to treat moderate-to severe acne
vulgaris was studied in clinical trial (NCT01498874)(64).

Gevokizumab/(XOMA 052) Human anti-IL-17A monoclonal antibody, CJM112

IL-1b is a potent mediator of inflammatory responses. P. acnes is Kelhala et al. demonstrated the presence of IL 17A positive T cells
capable of activating inflammation by indirectly increasing IL-1b and the activation of Th17-related cytokines in acne lesions (65).
 JOURNAL OF DERMATOLOGICAL TREATMENT 7

Table 4. Future of acne therapy – anti-inflammatory agents.

Name of drug
NO-np/nitric oxide-releasing
nanoparticle
PDE inhibitor: Apremilast
SCIO-469: inhibitor of the a
isoform of p38 mitogen-
activated protein kinase
(p38 MAPK)
XOMA 052/Gevokizumab:
humanized monoclonal IgG2
antibody with high affinity
and specificity to IL-1b
CJM112: human anti-IL-17A
monoclonal antibody
Vitamin D analog
Study year Purpose of study
2014 To utilized an established
nanotechnology capable of
generating/releasing nitric oxide
over time (NO-np).
2010 To determine the safety and
efficacy of 20 mg apremilast
taken twice a day for 12 weeks
in the treatment of moderate-
to-severe acne
2014 To investigate whether P. acnes-
induced proinflammatory
cytokine release is mediated by
P. acnes-induced activation of
p38 mitogen-activated protein
kinase (p38 MAPK) in human
keratinocytes.
2011 To evaluate the efficacy and
safety of gevokizumab in
moderate to severe acne
2016 To assess preliminary efficacy
and safety of CJM112 in patients
with moderate to severe
inflammatory acne and to
determine if CJM112 has an
adequate clinical profile for
further clinical development
2012 To determine the clinical
efficacy of a topical vitamin D
analog (Calcipotriene) on acne
Study design
Experimental in vitro and in
vivo study
Phase 2, open label, single-
group assignment study
(NCT01074502)
Experimental study (in
vitro study)
Phase 2, randomized, double-
blind placebo-controlled study
(NCT01498874)
A randomized, double blind,
placebo-controlled, multi-center,
parallel group study
(NCT02998671)
Phase 2/3, randomized, double-
blind, single-group clinical trial
(NCT01694433)
Result
P. acnes was found to be highly
sensitive to all concentrations of
NO-np. NO-np significantly
suppressed IL-1b, TNF-a, IL-8,
and IL-6 from human monocytes
and IL-8 and IL-6 from human
keratinocytes, respectively.
Study terminated for lack
of funding
Propionibacterium acnes induced
activation of p38. Inflammatory
cytokine/chemokine secretion in
keratinocytes is dose-
dependently inhibited by
SCIO-469
No official results have been
posted in ClinicalTrials.gov
Ongoing
No official results have been
posted in ClinicalTrials.gov

A clinical trial (NCT02998671), to assess preliminary efficacy and References

safety of human anti-IL-17A monoclonal antibody, CJM112, in
patients with moderate to severe inflammatory acne is 1.
ongoing (66).
2.
Vitamin D (VD) analogs
Sebocytes have been identified as bioactive VD-responsive target 3.
cells. Cultured sebocytes after treatment with VD showed signifi-
cant decrease in the expression of IL-6, IL-8, and matrix metallo-
proteinases 9 (67). A clinical trial (NCT01694433), to determine the 4.
efficacy of calcipotriene cream in the treatment of acne is cur-
rently being conducted (68).
5.
Conclusions 6.
Newer evidence that sebocyte activity being controlled via a
range of cellular pathways apart from androgen alone, dietary 7.
influence on acne, emphasizes the complex pathogenesis of acne.
The role of P. acnes biofilm in the formation of acne and treat-
8.
ment resistance cannot be ignored. With emerging P. acnes resist-
ance towards antibiotics, the traditional practice of mainly
targeting the role of P. acnes in the development of acne, may no
longer suffice. There is urgent need for more translational
research and clinical studies for development of newer treatment
modalities that can target the emerging concepts in pathophysi- 9.
ology of acne.
10.
Disclosure statement
The author reports no conflict of interest.
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