Antimicrobial Resistance

Describe the principles of anti-microbial resistance

Resistance occurs when the maximal level of the agent tolerated is insufficient to inhibit growth.

Resistance can occur broadly via two mechanisms:

• Genetic Alteration
  • Spontaneously, through mutation and subsequent natural selection of resistant organisms
  • Transferal of resistance genes from organism to organism via plasmids

• Protein Expression
  Increasing or decreasing expression of proteins with subsequent change in efficacy of antimicrobials.

Mechanisms

Specific mechanisms of resistance (which may be genetic alterations or changes in protein expression) include:

• Prevent access to target
  • Decrease permeability
    • Narrowing of porin channels
      e.g. Streptococcal resistance to penicillins typically occurs by reducing access to PBPs.
    • Loss of non-essential transporter channels
      e.g. Anaerobes have no oxygen-transport channel which prevents penetration by aminoglycosides.
  • Active efflux of agent
    Increased efficiency or expression of efflux pumps. Can be:
    • Removed from cell
    • Trapped between cell wall layers
      e.g. Glycopeptide resistance in VRSA.

• Alter antibiotic target site
  • Changes in binding site protein will increase resistance to agents with low affinity
  • Over-expression of target protein
  • Synthesis of target-protecting proteins

• Modification or Inactivation of Drug
  • Metabolism of drug
    e.g. β-lactamases hydrolyse β-lactam rings

• Modification of Metabolic Pathways
  • Development of metabolic pathways to bypass site of action of antibiotic
    e.g. Resistance to Trimethoprim-Sulfamethoxazole by allowing bacteria to synthesis or absorb folic acid.

References

1. Harvey RA, Cornelissen CN, Fisher BD. Lippincott Illustrated Reviews: Microbiology (Lippincott Illustrated Reviews Series). 3rd Ed. LWW.
2. CICM September/November 2008
3. Blair JM, Webber MA, Baylay AJ, Ogbolu DO, Piddock LJ. Molecular mechanisms of antibiotic resistance. Nat Rev Microbiol. 2015 Jan;13(1):42-51. doi: 10.1038/nrmicro3380.
4. Microrao - Mechanisms of Antimicrobial Resistance