Pharmaceutical Microbiology: Antibiotics Resistance

Antimicrobial Resistance

• Antimicrobial resistance is the ability of microorganisms to survive and reproduce in the presence of antimicrobial agents that were previously thought to be effective against them.

Classification of Antibiotic Resistance

• Intrinsic resistance: due to bacterial structural or functional features, naturally occurring, species or genus specific.
  • Examples: Gram-negative bacteria are intrinsically resistant to vancomycin, aerobic bacteria are intrinsically resistant to metronidazole.
• Acquired resistance: can take place by two different mechanisms: mutations and horizontal gene transfer.
  • Present only in certain strains of a species or genus.

Mechanisms of Resistance

• Modification of the drug: production of enzyme that destroys or deactivates drug.
  • Examples: β-lactamases convert penicillins and cephalosporins into penicilloic and cephalosporic acids.
• Alteration of the target: alter target of drug so it binds less effectively.
  • Example: methicillin resistance in S. aureus (MRSA) due to the acquisition of mecA gene encodes PBP2a, that has low affinity for all β-lactams.
• Reduced cellular uptake: slow or prevent entry of drug into the cell.
• Increased efflux: pump antimicrobial drug out of the cell before it can act.

Common Misuses of Antibiotics

• Over-prescribing of antibiotics.
• Prolonged prophylactic therapy.
• It is too toxic to be given by injection.

Mechanism of Action of Antifungal Drugs

Azoles

• Inhibit ergosterol synthesis by inhibiting the fungal cytochrome P-450 3-A dependent enzyme 14-alpha demethylase, blocking the demethylation of lanosterol to ergosterol.
  • Accumulation of toxic intermediate sterols.
  • Increased membrane permeability, cell death.

Triazoles

• Fluconazole, itraconazole, posaconazole
• All are orally active, except posaconazole, which is available in injection form.

Nucleic Acid Synthesis

• Flucytosine is absorbed into fungal cells via cytosine permease and converted to 5-fluorouracil, which interferes with fungal RNA biosynthesis.
  • Used to treat systemic Candida spp. or Cryptococcus spp. infections.

Cell Mitosis

• Griseofulvin is a mitotic inhibitor that binds to polymerized fungal microtubules, inhibiting the de-polymerization, and leading to the failure of the fungal cell replication.
  • Used to treat dermatophytoses of the skin, hair, and nails.