Chemical-mediated alteration of antibiotic susceptibility: mechanisms and potential new targets for antibiotic adjuvant discovery

ABSTRACT The critical rise in antimicrobial resistance rates, coupled with a nearly stagnant drug discovery pipeline, has resulted in a sharp surge in clinical failure of antibiotic therapy. Antimicrobial resistance, possibly leading to therapeutic failures, has been predominantly attributed to genetically encoded intrinsic or acquired resistance determinants. However, small molecules that bacteria may be exposed to at the infection site have been implicated in antibiotic resistance, tolerance, and persister formation. Such chemicals, either produced by the host or bacteria, typically elicit transient effects on antibiotic responses while bacteria are exposed to them; as such, their effects may alter therapeutic outcomes but would not be detected in standard in vitro antibiotic susceptibility tests. Chemicals produced by certain bacteria may alter the response of the same or other bacterial species at the site of infection, potentially providing communal protection from antibiotic treatment. Notably, biosynthesis, uptake, and response mechanisms to such chemicals are genetically encoded; thus, these determinants may constitute potential drug targets to circumvent chemical-mediated resistance. This review aims to provide an update on small molecules that alter antibiotic responses, the molecular mechanisms thereof, and the recent progress made in the discovery of antibiotic adjuvants targeting these pathways.