‫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

Ribosome
Purines Pyrimidines
50S & 30S

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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