Antibiotics that target Cell Wall Synthesis

Drug Description/Mode of Action Resistance? Use

Fosfomycin and Fosmidomycin
Cycloserine
Bacitracin
Vancomysin and teicoplanin
 Inhibits the enzyme,
enolpyruvate transferase,
that catalyzes the
formation of UDP-N-
acetyl muramic acid from
UDP-N-acetyl-
glucosamine
 Inhibits the Alanine
racemase enzyme that
convers L-alanine to D-
alanine
 The D-Ala-D- Ala ligase
that joins together two D-
Ala molecules
 Peptide antibiotic
 Inhibits this
dephosphorylation with the
help of a metal ion such as
Zn or Mg (metal chelators
could diminish activity)
 Not absorbed orally and
remains in gut
 Glycopeptides
 Interrupt cell wall
synthesis by binding to the
D-Ala-D-Ala portion of
the murein monomer,
thereby inhibiting addition
of further monomers to it
 Effective against Gram (-)
bacteria that causes UTIs
 Antibacterial synergy in
vitro with beta-lactams,
aminoglycosides and
fluoroquinolones
 Also active against Gram
(+), especially
Vancomycin resistant
E.faecium and E.faecalis
2nd line agent used to treat multi-
drug resistant
 Bactericidal or
bacteriostatic depending
on infection site and
susceptibility of organism
Mycobacterium tuberculosis
Treats C.difficile colitis or to
eradicate VRE in the GI tract
 Bactericidal
 Activity against Gram (+)
and (-)
 Enzymes form D-Ala-D-  Bactericidal against
lactate which does not bind Gram (+) cocci and rods
to the glycopeptide  IV treatment of MRSA
antibiotics  Oral treatment of C.
 It also degrades any difficile colitis
residual D-Ala-D-Ala  Teicoplanin not used
 Bacteria have a thicker clinically in the US
peptidoglycan in which
 increased amounts of D-
Ala-D-Ala can act as a
decoy target for the drugs
Telavancin  Lipoglycopeptide 1. Enzymes for D-Ala-D-  IV treatment of serious
 Interrupt cell wall lactate (instead of D-Ala- skin infections caused by
synthesis by binding to the D-Ala) which does not Staph and Strep
D-Ala-D-Ala portion of bind to the glycopeptide  Bactericidal
the murein monomer, antibiotics  Activity against Gram
thereby inhibiting addition 2. Also degrades any residual (+)
of further monomers to it D-Ala-D-Ala  Active against MRSA
 The lipid portion of the
drug interacts with the
bacterial cell membrane,
thereby enhacing drug
binding and causing
depolarization of the cell
membrane
 More potent than Vanco
 Antibiotics that Target Replication
Drug Description/MOA
Quinolones  Inhibits bacterial
-Nalidix acid Topoisomerase type 2
name of the newer ones end in -  Inhibit DNA gyrase in Gram
floxacin negative bacteria
 Inhibit Topoisomerase type
4 in Gram positive bacteria
Rifampin (rifampicin)  Kills both extracellular
bacteria as well as bacteria
that are within phagosomes
 It targets the beta subunit
of DNA dependent RNA Pol
and blocks elongation, once
the RNA transcript reaches
a length of 2 or 3
nucleotides
Fluoroquinolones (-oxacin)  Inhibits helicase and
thereby DNA replication
 Readily absorbed from the
intestine
 4 generations
Resistance? Uses
 Mutation in gene for type 2 Infections caused by Gram – bacteria
topoisomerase E.coli
 Mutation in expression of Klebsiella pneumoniae
outer membrane porin Campylobacter jejuni
proteins Pseudomonas aeruginosa
 Efflux pumps that will pump Neisseria gonorrhea
the antibiotic out of the cell Enterobacter
Salmonella
Shigella
 Affect the bidning site of Treat TB and other mycobacterial
Rifampin on the RNA Pol diseases
 To counter this, treatment
of mycobacteria constitutes
combination therapy
 Antibiotics that target the 30S Subunit
Name Description/MOA
Aminoglycosides Bind to 16S rRNA within the 30S
subunit
Allows incorrect tRNAs to bind to
the mRNA
They act synergistically with beta-
lactams (inhibiting cell wall
synthesis)
Spectinomycin Binds to 16S rRNA within the 30S
subunit
Inhibits translocation
Bacteriostatic
Tetracyclines and Glycylcyclines Bacteriostatic
Bind to the 16S rRNA of 30S
subunit and blocks binding of
aminoacyl tRNA to the A site;
blocking addition of further amino
acids
Drugs inhibit protein synthesis of
mammalian cells in vitro, they have
no effect in vivo
Resistance? Use
1. plasmids code for Used mainly to treat Gram (-)
transferase enzyme or bacterial infections
enzymes that modify Strwptomycin, neomycin,
aminoglycosides by kanamycin, tobramycin,
adenylating, acetylating or paromomycin,
phosphorylating it gentamicin,netilmicin and
2. aminoglycoside entry can amikacin
be blocked by eliminating Not active against anaerobes and
certain outer membrane many Gram positive bacteria
porin proteins or other
membrane proteins
involved in drug transport
3. the site of drug interaction
on the 30S subunit can be
modified by mutation or
by a plasmid coded
enzyme
1. increased drug efflux or
decreased drug influx
2. bacteria produced
proteins that interfere
with the binding of these
drugs to the 16S rRNA
3. bacteria produce an
enzyme that inactivates
the drug
 Antibiotics that Target the 50S Subunit
Drug Description/MOA
Macrolides Semi synthetic derivatives of
erythromycin into azithromycin
and clarithromycin
Have excellent lung tissue
preparation
Show intracellular activity against
Legionella
Bacteriostatic
Target the 23S rRNA of the 50S
subunit (block the exit tunnel)
Ketolides Semisynthetic derivative of
Erythromycin into telithromycin
Has a higher affinity for the 50S
subunit as it binds to an additional
site on the 23S rRNA
Chloramphenicol Bacteriostatic
Binds to 23S rRNA and inhibits
peptide bond formation (interferes
with proper positioning of the
aminoacyl moiety of tRNA in the A
site
Lincosamides Interacts with the A site and P site
(clindamycin) and blocks peptide bond formation
Implicated as a potential cause of
pseudomembranous colitic caused
by C. difficile superinfection
Streptogramins Bind to the peptidyl transferase
(dalfopristin –Group A) center of 23S rRNA
(quinupristin –Group B) Bactericidal
Resistance Use
 Gram (-): production of
esterases that hydrolize
macrolides; chromosomal
mutation to modify the
ribosome binding site;
increase active drug efflux;
reduce permeability of
membrane to macrolides
 Gram (+): production of
methylase which modifies
the ribosome such that
macrolide shows
decreased binding
1. Plasmid encoded Haemophilus influenza
acetyltransferases Neisseria meningitides
inactivates the drug Some strains of Bacteroides
2. Decreased permeability to Toxicity: drug also inhibits
the drug mitochondrial protein synthesis,
causing toxicity in patient
Useful in treating Bacteroides
infections and mixed infections
involving anaerobes
Treatment of serious infections
caused by Vancomycin resistant
Enterococcus faecium or
Streptococcuc pyogenes
 Oxazolidinones Binds to the A site at a region Mutations in 23S rRNA Effective against drug resistance
(linezolid) where the aminoacyl tRNA Gram + bacteria (MRSA, penicillin
normally binds resistant, Streptococci,
Vancomycin resistant Enterococci
Pleuromutilins Bind to a pocket in the A site of the Once elongation has begun and Topical treatment for bacterial
(retapamulin) peptidyl transferase active center the A and P sites are occupied, the skin infections
where aminoacyl tRNA normally drug is no longer active
binds; binding extends into the P
site

INHIBIT CELL MEMBRAE STABILITY
Daptomycin: cyclic lipopeptide antibiotic
 Integrate into Gram + cell membrane
1. Oligomerization of daptomycin
2. Formation of pores
3. K efflux, membrane depolarization
4. Cell death
 Can treat MRSA
Polymyxins: fatty acid portion of the drug
penetrates into the hydrophobic portion of the
outer membrane of gram – bacteria
 Primarily used for external treatment
of localized infections (eye and skin
infections)
 Used primarily for gram – and not
gram +
More Antibiotics
INHIBIT BACTERIAL METABOLITES
Sulfonamides: structure analogs of PABA
 Interfere with microbial growth by
competitively inhibiting incorporation
of PABA into folic acid
 Broad spectrum and is effective for
gram +, gram -, and Chlamydia
Trimethoprim: structural analog of DHF acid
 Inhibits the synthesis of folic acid but at
a different point in the pathway
 Combination with sulfamethoxazole
results in a synergistic inhibition of the
folic acid pathway
 Broad spectrum activity and is used
w/ sulfamethoxazole for aerobic and
facultative gram + and gram -
bacgteria
INHIBIT MYCOBACTERIAL GROWTH
Ethambutol: Bacteriostatic
Inhibits arabinosyl transferase and decreases
arabinogalactan synthesis
Pyrazinamide
Isoniazid
Inhibit mycolic acid synthesis
Bactericidal (isoniazid)
Resistance: chromosomal mutations; have
extended spectrum beta-lactamases and are
highly resistance to most beta-lactams
Rifampin
Streptomycin (aminoglycoside)
 Bacterial Vaccines
Name Dosage/Immunity Treated for:
DTaP Does not give lifelong immunity Protects against:
Boost every 10 years Diphtheria
Tetanus
Pertussis
Hib  Babies and children < 5 years old are Hib disease caused by Haemophilus influenzae
most at risk
 Children > 5 years old and adults do
not need vaccine
PCV13  Recommended for use in infants and 13 types of pneumococcal bacterial
young children (Streptococcus pnuemoniae) that cause most
 Certain older children may also need a of the severe disease in children
dose of PCV13
 Recommended for all adults > 65 years
 Also recommended for adults > 19 with
HIV infection, organ transplantation,
leukemia, lymphoma, severe kidney
disease
PPSV23  Recommended for all adults > 65 years 23 serotypes of Strep pneumoniae
and for those > 2 years at high risk for
disease
 Also recommended for adults 19-64
years old who smoke cigarettes or who
have asthma
Meningococcal  All 11 to 12 year olds should be Meningococcal bacteria
1. Meningococcal conjugate vaccine vaccinated with a meningococcal
(Menactra, Menveo, and MenHibrix) conjugate vaccine
2. Meningococcal polysaccharide vaccine  A booster dose is recommended at age
(Menomune) 16 years
3. Serogroup B meningococcal vaccines  Teens and young adults (16-23) also
(Bexsero and Trumenba) may be vaccinated with a serogroup B
meningococcal vaccine