9. Antibiotics MOA

• Inhibit cell wall synthesis by blocking peptidoglycan crosslinking

  • β-lactam mimics the D-ala-D-ala structure of bacterial peptidoglycan residue.

  • β-lactam irreversibly binds to penicillin-binding proteins (PBPs) which act as transpeptidases → stalled cross-linking of peptidoglycan in cell wall (β-lactam cannot be cleaved) → inability to synthesize new cell wall during replication → bacterial death (bactericidal effect)

• Activate autolytic enzymes

intrinsically β-lactamase resistant through the addition of bulky side chains (e.g., isoxazolyl), which prevent bacterial β-lactamase from hydrolyzing the β-lactam ring

• The molecular structure is similar to penicillin and therefore susceptible to degradation by β-lactamase (β-lactamase sensitive).

• Oral bioavailability of amoxicillin is greater than that of ampicillin

bind to 23S ribosomal RNA molecule of the 50S subunit → blockage of translocation → inhibition of bacterial protein synthesis (bacteriostatic effect)

Binding to the 50S subunit causes peptidyl-tRNA to dislocate from the ribosome during the elongation phase, resulting in inhibited protein synthesis.

• Inhibition of bacterial folic acid synthesis

  • Sulfonamides inhibit dihydropteroate synthase.

  • Diaminopyrimidine derivatives inhibit dihydrofolate reductase (DHFR).

    • DHFR uses NADPH to reduce dihydrofolic acid to tetrahydrofolic acid (THF).

    • THF can be converted to methylene-THF.

    • Methylene-THF is an important cofactor for thymidylate synthetase, which catalyzes the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP).

• Both are bacteriostatic but become bactericidal when combined (sequential block of folate synthesis)

• Bind to 30S subunit of the bacterial ribosome → irreversible inhibition of initiation complex → inhibition of bacterial protein synthesis → cell death (bactericidal effect)

• Misreading of mRNA

• Blockage of translocation

• Synergistic effect when combined with β-lactam antibiotics: β-lactams inhibit cell wall synthesis → facilitated entry of aminoglycoside drugs into the cytoplasm

• —> Beta-lactam ABs

• Inhibit cell wall synthesis by blocking peptidoglycan crosslinking

  • β-lactam mimics the D-ala-D-ala structure of bacterial peptidoglycan residue.

  • β-lactam irreversibly binds to penicillin-binding proteins (PBPs) which act as transpeptidases → stalled cross-linking of peptidoglycan in cell wall (β-lactam cannot be cleaved) → inability to synthesize new cell wall during replication → bacterial death (bactericidal effect)

• Activate autolytic enzymes

—> Beta-lactam AB

inhibition of prokaryotic topoisomerase II (DNA gyrase) and topoisomerase IV→ DNA supercoiling → formation of double-stranded breaks → inhibition of DNA replication and transcription (bactericidal effect)

bind 30S subunit → aminoacyl-tRNA is blocked from binding to ribosome acceptor site → inhibition of bacterial protein synthesis (bacteriostatic effect)

• Bind terminal D-ala-D-ala of cell-wall precursor peptides → inhibition of cell wall synthesis (peptidoglycan formation) → bacterial death (bactericidal effect against most gram-positive bacteria)

• Bacteriostatic against C. difficile

binds to 50S subunit → blockage of peptide translocation (transpeptidation) → inhibition of peptide chain elongation →inhibition of bacterial protein synthesis (bacteriostatic effect)

reduced by bacterial nitroreductases to reactive metabolites → bind to bacterial ribosomes → impaired metabolism, impaired synthesis of protein, DNA, and RNA → cell death (bactericidal effect)