Mechanisms of Antimicrobial Resistance

Mechanisms of Antimicrobial Resistance

1. Definition & framing

• Drug resistance is the unresponsiveness of a microorganism to an antimicrobial agent (AMA) to which it was originally sensitive; it is akin to the phenomenon of tolerance seen in higher organisms (KDT 8e Ch.50, pp.742–3).
• Resistance is the inevitable evolutionary consequence of antimicrobial use: when a microbial species is subjected to an existential (chemical) threat, that selection pressure preserves random genomic variants that permit survival — today every major class of antibiotic is associated with emergence of significant resistance (G&G 14e Ch.56, p.1133).
• Antibiotics work in concert with the host immune system; mechanisms that interfere with the immune response can produce an effect similar to classical resistance even without altering the drug–target interaction (G&G 14e Ch.56, p.1133).
• More than one mechanism frequently operates simultaneously in a single resistant isolate, and a single resistant phenotype may be reached by several independent molecular routes (G&G 14e Ch.56, p.1133).
• Mechanistic axis (G&G three-tier scheme): antimicrobial resistance can arise at any step in the process by which a drug reaches and combines with its target — three major mechanisms plus a set of less-common ones (G&G 14e Ch.56, p.1133):
  • reduced concentration of antibiotic at its target site;
  • enzymatic alteration or destruction of the antibiotic;
  • alteration of the antibiotic target so that drug affinity falls.
  • Less-common mechanisms: bypass of the inhibited metabolic pathway, excision of antibiotic–target complexes, and overproduction of the target enzyme (G&G 14e Ch.56, p.1133).
• Genetic axis (origin of the resistance determinant): resistance is either intrinsic/natural (pre-existing, species-level) or acquired, the latter by mutation–selection (vertical) or horizontal gene transfer (infectious resistance) (KDT 8e Ch.50, pp.742–4; G&G 14e Ch.56, pp.1134).
• These two axes are orthogonal — e.g. an efflux pump (biochemical "reduced concentration") may be encoded chromosomally by mutation OR carried on a plasmid acquired horizontally; both must be specified to fully describe a resistant strain.