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• Antibiotic


  A medicine that inhibits the growth or destroys bacteria
• Types of antibiotics


  • Bacteriostatic: Inhibit multiplication
  • Bactericidal: Kill bacteria
• What do antibiotics target in bacteria?


  • Cell wall synthesis
  • Membrane synthesis
  • Protein synthesis
  • Metabolic pathways
  • Nucleic acid synthesis
• Bacterial cell wall structure


  • Polysaccharide backbone
  • Peptide crosslinks
• Mechanism of action of penicillin


  Zeng & Lin, 2013, Frontiers in Microbiology
• Types of penicillins


  • Natural penicillins
  • Broad spectrum penicillins
  • Reverse spectrum penicillins
  • Extended spectrum penicillins
  • β-lactamase resistant penicillins
• Broad spectrum penicillins


  Effect exerted through penicillin binding protein, used to treat septicaemia, pneumonia, meningitis, most given parenterally, IM or IV, excretion largely via kidney, can cause nephrotoxicity & diarrhoea
• Cephalosporins


  • Cefaclor, Cephalexin, Cefotaxime
• Penicillin resistance mechanisms


  • Production of β-lactamases
  • Modification of penicillin-binding proteins
• Other antibiotics that target the cell wall

  • L-Ala to D-Ala
• Antibiotics that inhibit protein synthesis


  Competitively binds the A site, broad spectrum of activity, resistance a growing problem (efflux, ribosomal protection or tetracycline inactivation)
• Tetracyclines


  Bacteriostatic, competitively binds the A site, broad spectrum of activity, resistance a growing problem
• Aminoglycosides


  Bactericidal, interferes with mRNA translation, activity enhanced by penicillins, poorly absorbed in the gut must be given IV/IM, adverse effects: ototoxicity, nephrotoxicity, resistance: AMEs, target modification, efflux
• Macrolides


  Bacteriostatic, binds 50s subunit, prevents translocation, most effective against Gram positives, metabolised by demethylation in liver CYP3A4, adverse effects: heart arrhythmias & GI disturbance, resistance: efflux or methylation of ribosomal targets
• Chloramphenicol


  Bacteriostatic / Bactericidal, inhibits transpeptidisation reaction, broad spectrum of activity, resistance: enzymatic inactivation via acetyltransferase, efflux, ribosomal mutations, oral / IV, side effects: Gray Baby Syndrome, bone marrow suppression, metabolised in liver
• Folate synthesis and utilisation


  Separate steps of the same pathway hence frequently used together, bacteriostatic
• Sulphonamides


  Folate biosynthesis inhibition, broad spectrum, resistance: dihydropteroate synthetase with low affinity, well distributed inc. CSF, crosses Blood-brain barrier, N-acetylated in liver
• Dihydrofolate reductase inhibitors


  Selective toxicity, 52,000x IC50 concentration, trimethoprim specific for bacterial isoform of enzyme, oral, resistance: low affinity dihydrofolate reductase, most common use: UTI & respiratory tract infections
• Fluoroquinolones


  Inhibits DNA Gyrase, oral and well absorbed, does not cross BBB, broad spectrum: Gram +ve & -ve and enterobacteria, inhibits CYP1A2, adverse effects: GI effects, prolongation of QT interval
• Mycobacteria: Tuberculosis & Leprosy


  • Nonmotile, slow growing, have very thick, waxy, lipid-rich hydrophobic cell walls, contain mycolic acids in their cell wall, can survive in macrophages, becoming a major problem in immunocompromised patients
• Tuberculosis (TB) the 13th leading caused of death worldwide. 2021: 10.6 million contracted TB, 1.6 million died from the disease (187000 with HIV), 1.2 million children contracted TB. Multidrug-resistant TB (MDR-TB) remains a public health crisis and a health security threat. TB incidence was falling at about 2% per year but has increased since 2021 due to the impact of COVID-19. Ending the TB epidemic by 2030 is among the health targets of the WHO.
• Rifampicin


  Potent inducer of CYP3A4, increased degradation of glucocorticoids & warfarin, inhibits prokaryotic DNA-dependent RNA polymerase, a semisynthetic derivative of rifamycin, oral, crosses BBB, good against Gram positives, Gram negatives and Mycobacteria
• Daptomycin


  Lipopeptide, approved 2003, insertion into the membrane leading to cell death, Gram positive including MRSA, VRSA, poorly absorbed – given IV; Half life: 8-9hrs (up to 28hrs with renal impairment), eliminated mainly via renal excretion, can cause damage to musculoskeletal system, eosinophilic pneumonia and peripheral neuropathy
• Dihydrofolate reductase


  Enzyme necessary for folate utilisation
• Dihydropteroate synthase


  Enzyme necessary for folate synthesis
• Folate synthesis and utilisation


  Essential for DNA synthesis and repair in bacteria
• Trimethoprim


  Inhibits dihydrofolate reductase, necessary for folate utilisation
• Sulfonamides


  Inhibit dihydropteroate synthase, necessary for folate synthesis