Antimicrobial Drugs:

Mechanism of Action & Resistance

R. Lia Iswara, dr, MS, SpMK

Dept. of Microbiology
FK USU
 Selective toxicity

• Antimicrobial therapy:
selective inhibition of the growth of the micro
organism without damage to the host, eg,
Penicillin & Cephalosporin prevent the
synthesis of peptidoglycan , inhibiting the
growth of bacterial but not human cells.
• Broad spectrum antibiotics:
active agains several types of microorganisms,
eg, tetracyclin : active against many gram-
negative rods, chlamydia, mycoplasmas and
rickettsiae.

• Narrow-spectrum antibiotics:
active against one or very few types, eg,
vancomycin: primarily used against certain
gram-positive cocci (staphylococci and
enterococci).
 Bactericidal & Bacteriostatic activity

• A bactericidal drug kills bacteria.

• A bacteriostatic drug inhibits their growth

but does not kill them.
 Mechanisms of Action

1. Inhibition of bacterial cell wall synthesis.

2. Inhibition of bacterial protein synthesis.
3. Inhibition of bacterial nucleic acid synthesis.
4. Alteration of bacterial cell membrane function.
 1. Inhibition of bacterial cell wall synthesis.
• Penicillins :PNC-G, PNC-V
Methicillin, Oxacillin, Cloxacillin, Dicloxacillin,
Ampicillin, Amoxicillin, Carbenicillin, Ticarcillin,
Piperacllin, Mezlocillin.
• Cephalosporins:
1st Gen: Cefachlor, Cephalotin, Cephalexin
2nd Gen: Cefuroxim, Cefixime, Cefoxitin
3rd Gen: Cefotaxime, Ceftriaxone, Cefoperazone
4th Gen: Cefepime, Cefpirom
• Carbapenem: Imipenem
• Monobactam: Aztreonam
• Glycopeptide: Vancomycin and Teichoplanin
• Clycoserine: second-line drug anti tuberculosis
• Bacitracin: for superficial skin infection, but toxic for systemic
use.
 Mehanisms of action
• Inhibiting transpeptidase, enzyme that catalyze the final cross-
linking in the synthesis of peptidoglycan / bacterial cell wall.

• Penicillin bind to receptors in the bacterial cell membrane and

cell wall called Penicillin Binding Proteins(PBPs). Some PBPs
are transpeptidase.

• Penicillins, Cephalosporins, Carbapenem, Monobactam (β-

lactam drugs) β-lactam ring structure (essential for
antibacterial activity); Vancomycin, Cyclocerine & Bacitracin.

• Kill bacterial cells only when they are growing

 2. Inhibition of bacterial protein synthesis.

The differences between bacterial and human ribosomal protein:

• Bacterial cell: 70S ribosom with 50S and 30S subunits.
• Human cell : 80S ribosom with 60S and 40S subunits.

1. Drug that act on the 30S subunit:

-Aminoglycosides (Streptomycin, Gentamicin, Tobramycin,
Amikacin, Neomycin): inhibition of the initiation complex and
misreading of messenger RNA (mRNA).
-Tetracyclines: blocking the aminoacyl transfer RNA (tRNA)
from entering the acceptor site on the ribosome.

2. Drug that act on the 50S subunit: Chloramphenicol, Macrolide (Erythromycin,

Azithromycin, Clarithromycin), Clindamycin, Linezolid
3.Inhibition of bacterial nucleic acid synthesis
• Inhibition of precursor synthesis:
Sulfonamides: are structural analogues of p-
aminobenzoic acid(PABA).
Trimetroprim: inhibits dihydrofolate reductase.

• Inhibition of DNA Synthesis:

Quinolone (Ciprofloxacin,norfloxacin, ofloxacin):
inhibits DNA gyrase (topoisomerase).
Flucytosine: antifungal

• Inhibition of mRNA Synthesis:

Rifampin
4. Alteration of bacterial cell membrane function.

• Polymixin (polypeptide antibiotics): the

positively charged free amino group act
like cationic detergent to disrupt the
phospholipid structure of the bacterial cell
membrane.
• Amphotericin B, Nystatin,
Azoles(Fluconazole, Ketokonazole,
Itraconazole): alteration of ergosterol
(fungal cell membranes).
 Additional drug mechanisms:
• Isoniazide(INH): inhibit mycolic acid
synthesis (M. tuberculosis).
• Metronidazole(Flagyl): electron sink, inhibit
DNA synthesis.
• Ethambutol: bacteriostatic, inhibits
arabinogalactan(link between mycolic acid
and the peptidoglycan)
• Pyrazinamide(PZA): inhibits fatty acid
syntethase.
• Griseofulvin: antifungal drug, inhibit DNA
Synthesis.
 Mechanisms of Drug Resistance.
1. Inactive Drug : Cleavage by β-lactamase, penicillinase,
cephalosporinase, acetylase, adenylase, phosporylase.
2. Modify drug target in bacteria:
- Mutation in Penicillin-binding proteins(PBPs) : PNC.
- Mutation in protein in 30S ribosomal subunit :Strept.
- Replace alanine with lactate in peptidoglycan:Vanco.
- Mutation in DNA gyrase : Quinol.
- Mutation in RNA polymesare : Rifamp.
- Mutation in catalase-peroxidase : INH
3. Reduce permeability of drug : Mutation in porin proteins
:Pnc, Aminog.
4. Export of drug from bacteria: Multidrug resistance pump
:Tetra, Sulfon.
 Genetic Basis of Resistance
1. Chromosome-mediated resistance/ chromosomal
mutation: mutation in the gene that code the target
of the drug or the transport system that control the
uptake of the drug.

2. Plasmid mediate resistance: have two set of genes

(Resisten transfer genes that code sex pilus and
drug resistance genes), eg, gen tet, strep, pen,
chloro, erythro, gent.

3. Transposon-Mediated Resistance: gene that

transferred either within chromosomal DNA and
plasmid.
 R plasmid-mediated resistance mechanisms
Drug Mechanisms of Resistance
Penicillin β-lactamase cleavage of β-lactam ring
Aminoglycosida Modification by acetylation,adenylation
or phosphorylation
Chloramphenicol Modification by actetylation
Erythromycin Change in receptor by methylation of
rRNA
Tetracycline Reduce uptake or increase export
Sulfonamide Active export out of the cell and
reduced affinity of enzyme
 Non Genetic basis of resistance
1. Adjunct Bacteria within an abscess cavity, the drug
cannot penetrare effectively. Surgical drainage is
therefore a necessary adjunct to chemotherapy.
2. Bacteria in resting state, ie not growing.
3. Lose their cell wall, survive as protoplasts.
4. Administration of the wrong drug or wrong dose.
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