Mechanisms of action of

antibiotics and synthetic

anti - infective agents

 Introduction
Sites of Action of
the classes of
Antibiotics
1. The microbial cell wall
2. Cytoplasmic membrane
3. Protein synthesis
4. Chromosome function
and replication
5. Folate antagonist
The microbial cell
wall

Peptidoglycan biosynthesis in bacteria
and its inhibition
Composed of sugar (glycan) chains
o Alternate of N - acetylmuramic acid and N
acetylglucosamine

D-isomers
o ( D-alanine, D-glutamic acid)

Amino acid (unusual)

o meso-diaminopimelic acid
Inhibition of Cell Wall
Synthesis
Agents that target the peptidoglycan layer
Antimicrobial Agents
o Beta Lactam Drugs
o Glycoproteins
o D-Cycloserine
o B-Lactamase inhibitors
 B-Lactam
MOA: attachment to PBP penicillin binding
protein, inhibition of transpeptidation rx
o Target PBP or transpeptidase enzyme

The final stage of peptidoglycan assembly is the cross-

linking of the linear glycan strands in the cell wall
o Transpeptidase enzyme responsible for the glycan X-link formation

The - lactam antibiotics inhibit transpeptidases by

acting as alternative substrates (mimic the D-alanyl-D-
alanine)
o The ability of Beta Lactam Drugs to bind to enzymes (PBP) is due to
its structural similarity to D-alanyl D-alanine
 B-Lactam Drugs:
o Penicillin
Penicillin G
Penicillin V
o Aminopenicillins (ex. Ampicillin, amoxicillin)
o Cephalosporins
o Carbepenems
o monobactams
 Glycopeptides
MOA: Binds to terminal D-Alanyl-D-
Alanine (D-ala-D-ala) of the
pentapeptidyl-glycosyl peptidoglycan
intermediates
o Target: peptidoglycan precursor (substrate): D-ala-D-ala
o Substrate is used to form cross-link
o Glycopeptides block this process by binding to the
disaccharide peptidoglycan precursor, D-alanyl - D-
alanine

Works by inhibiting the transpeptidation step of

cell wall synthesis
No cell wall formed
 GLYCOPEPTIDES
o Activity is Limited to Gr (+) Organisms
Treatment of Infections caused by staphylococci,
streptococci and enterococci

Vancomycin
o Big molecule
Teicoplanin
 Cycloserine
MOA: inhibit the synthesis of the
peptidoglycan precursors in the cytoplasm
by inhibiting racemase enzyme
- converts (L-alanyl - D-alanine)

Cycloserine prevents forming D-alanyl-D-

alanine
 -Lactamase inhibitors
clavulanic acid,
sulbactam and tazobactam
Expression of - lactamase enzymes is the most
important mechanism through which organisms
become resistant to B-Lactams
Inhibitors: clavulanic acids, sulbactam, tazobactam
(combinations) amoxicillin, ampicillin, peperacillin

Use in combination protecting them from inactivation

by the lactamases

Inhibitors are hydrolysed by the - lactamases in the

same manner as susceptible lactam antibiotics
 arabinogalactan
biosynthesis in
mycobacteria
Mycobacteria wall
Peptidoglycan
Arabinogalactan polysaccharide
Lipids: mycolic acid, glycolipids, phospholipids,
waxes

Isoniazid and ethambutol - specific

antimycobacterial agents
 Isoniazid
Isoniazid interferes with mycolic acid synthesis
by inhibiting an enoyl reductase (InhA)

Isoniazid Converted inside the mycobacteria to a

free radical species by a catalase peroxidase
enzyme, KatG. The active free radicals then
attack and inhibit the enoyl reductase, InhA
 Ethambutol
The cell walls of mycobacteria contain an
arabinogalactan polysaccharide

Ethambutol blocks assembly of the

arabinogalactan polysaccharide by inhibition of
an arabinotransferase enzyme
 caspofungin,
anidulafungin and
micafungin
Antifungal agents
They interfere with the synthesis of the -1,3-d-
glucan polymer (fungal cell wall)

Without the glucan polymer, the integrity of the

fungal cell wall is compromised, yeast cells lose
their rigidity
Cytoplasmic
Membrane

 MOA: Act like detergents which
interact with phospholipids.
Increasing permeability
Leading to Leakage of
macromolecules and ions
essential for cell survival
 Not used systemically: (damage cells)
o skin antiseptics, disinfectants, preservatives

Therapeutic use:
o Polymyxins, polyenes, imidazoles, triazoles,terbinafine
 Polymyxins
Polymyxin E (colistin) is used in the treatment of
serious Gram - negative bacterial infections
(Psedomonas aeruginosa, Acinetobacter infection)

The polymyxin molecules - penetrate to the

cytoplasmic membrane, bind to phospholipids,
disrupt membrane integrity, and cause irreversible
leakage of cytoplasmic components

Detergent-like properties - damaging action

 Daptomycin
The compound inserts itself into the
cytoplasmic membrane and drug molecules
aggregate together forming channels

The leakage of potassium ions from the cells

results in inhibition of macromolecular synthesis
and cell death
 Polyenes
Amphotericin B and nystatin are the most
commonly used members of this group of
antifungal agents

Derive their action from their strong affinity

towards sterols, particularly ergosterol (fungal
membrane)

Polyene is pulled into the membrane interior,

destabilizing the structure and causing leakage of
cytoplasmic constituents (K, AA, nucleotides)
Results to cell death
 Imidazoles and
Triazoles
The azole antifungal drugs act by inhibiting the
synthesis of the sterol components of the
fungal membrane

Cause rapid defects in fungal membrane integrity

due to reduced levels of ergosterol
 Terbinafine
Synthetic antifungal agent
Inhibits the enzyme squalene epoxidase at an
early stage in fungal sterol biosynthesis

Terbinafine causes accumulation of unsaturated

hydrocarbon and decrease of ergosterol in
fungal cell membrane