‫بسم ال الرحمن الرحيم‬

Mechanisms of actions of
antimicrobial drugs

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 Introduction
• Strategies to combat microbes:
• Public health measures
• Screening procedures, early detection
• Vaccines
• Drugs
• Drugs therapy targets selective differences
between microbes and host cells

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 Selective targeting of microorganisms
• Targets unique to microbes & lack in host cells:
• Bacterial cell wall contains peptidoglycan strands
e.g. Penicillins ↓ cross linking of peptidoglycans
• Fungal cell membrane contains ergosterol
e.g. Azole antifungals ↓ ergoserol synthesis
• Targets similar to microbes & have quantitative
differences from the host cells:
• Different enzyme or receptor isoform
e.g.trimethoprim inhibits bacterial DHFR
& pyrimethamine inhibits malarial DHFR
• For selective targeting important to understand
mechanisms of actions of drugs
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 Mechanism of action of antimicrobials (overview)
Inhibitors of cell wall Inhibitors of cell membrane
synthesis synthesis
Pteridine

Folinic acid Folic acid PABA

mRNA
DNA
Inhibitors of protein Inhibitors of DNA
synthesis & cell division
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 Inhibitors of cell wall synthesis
• A. Inhibitors of synthesis of peptidoglycan:
• Bacterial cell wall contains peptidoglycan strands
• Peptidoglycan is composed of UDP-N-acetyl-muramic
acid, UDP-N-acetyl-glucosamine & a pentapeptide
• Cycloserine, resembels to alanine & inhibits addition
of alanine into peptide chain
• Vancomycin inhibits transglycosidase enzyme &
prevents peptidoglycan chain elongation

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 Inhibitors of cell wall synthesis (Cont.)
• B. Inhibitors of cross linking of peptidoglycan
strands:
• Beta-lactam antibiotics: e.g. Penicillins &
cephalosporins
• Inhibit transpeptidase enzyme, involved in cross
linking of peptidoglycan strands
• Also called as transpeptidation reaction &
strengthens cell wall.
• Defects in the synthesis of cell wall cause wholes in
cell wall & chnages in permeability
• Leading to bacterial swelling & lysis
• Hence cell wall synthesis inhibitors are bactericidal

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 Inhibitors of cell wall synthesis (Cont.)
• Inhibitors of mycobacterial cell wall:
• Mycobacterial cell wall is composed of arabino-
galactan chains
• Ethambutol inhibits arabinosyl-transferase enzyme
involved in addition of arabinose in arabino-galactan
chains
• Isoniazid & pyrazinamide inhibit synthesis of
mycolic acid for mycobacterial cell wall by inhibiting
fatty-acid synthase enzyme (FAS)

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 Inhibitors of cell membranes
• Inhibitors of fungal cell membrane
• A. Inhibitors of ergosterol synthesis
• Azole anti-fungals: e.g. fluconazole
inhibit fungal P-450 enzyme (14α- demethylase)
• Defects in synthesis causes wholes in cell membrane
• B. Ergosterol binding compounds
• Polyene anti-fungals: e.g. amphotericin B
Bind to ergosterol in the cell membrane & increase
membrane permeability
• Leakage of essential elements, cell lysis, fungicidal

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 Inhibitors of protein synthesis
• Protein synthesis takes place in ribosomes
• Bacterial ribosome consists of 30S & 50S sub-units
whereas, mammalian ribosomes have 40S & 60S
• Tetracyclines ↓ 30S ribosomal subunit & are
bacteriostatic
• Macrolides & chloramphenicol ↓ 50S ribosomal
subunit & are bacteriostatic
• Aminoglycosides ↓ 30S ribosomal subunit, but some
abnormal proteins insert in cell membrane & form
pores, thus become bactericidal
• Rifampin ↓ DNA dependent RNA polymerase & is
bactericidal
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 Inhibitors of DNA & cell division
• Antimicrobial drugs can affect microbial
DNA & cell division in following ways:
• Inhibit DNA synthesis
Inhibitors of folate synthesis
Inhibitors of thymidylate synthesis
• Inhibit DNA replication
• Inhibit microtubules & mitosis

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 Inhibitors of DNA synthesis
Folate precursors
(PABA, pteridine, glutamic acid)
- Sulfonamides & sulfones
Trimethoprim - Folic acid
Folinic acid

Purines Pyrimidines
(adenine & guanine) (cytosine & thymine)
Ribonucleotides
- Flucytosine
Deoxy-ribonucleotides

DNA 11
 Inhibitors of DNA synthesis (Cont.)
• A. Inhibitors of folate metabolism
• Folic acid (dihydro-folate) synthesis inhibitors:
Sulfonamides & sulfones inhibit dihydro-pteroate
synthase (DHPS) enzyme
• Folinic acid (tetrahydro-folate) synthesis inhibitors:
Trimethoprim inhibits dihydro-folate reductase
(DHFR) enzyme (bacterial DHFR more than human)

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 Inhibitors of DNA synthesis (Cont.)
• Synergism of folic acid (dihydrofolate) & folinic
acid (tetrahydro-folate) synthesis inhibitors:
• Sulfamethoxazole + PABA + pteridine
Trimethoprim Glutamic acid
Dihydro-pteroate
(anti-bacterial) Sulfamethoxazole ↓ synthase
Folic acid
Dihydro-folate
Trimethoprim ↓
reductase
Folinic acid

DNA
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 Inhibitors of DNA synthesis (Cont.)
• B. Inhibitors of thymidylate synthesis
• Flucytosine: is a cytosine analogue
• Converted in fungi & GI flora to 5-fluorouracil (5-FU)
• 5-FU converted to 5-FdUMP
dUMP
• 5-FdUMP incorporated to DNA TS
& inhibits thymidylate synthase (TS) dTMP

• ↓ DNA synthesis
DNA

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 Inhibitors of DNA replication & mitosis
• During cell division chromosomes line up in the
equator of cell
• Each divides into two (DNA- replication) by
topoisomerases (topoisomerase I to IV)
• Each part is pulled to opposite pole of the cell by
mitotic spindles made up of microtubules
• Quinolones inhibit bacterial topisomerase-II [ in
gram (-) bacteria] & topoisomerase IV [in gram (+)
bacteria], inhibit DNA replication & are bactericidal
• Griseofulvin inhibits microtubule assembly, mitotic
spindle formation, cell division & is bacteriostatic
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