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

## TL;DR

This paper reviews how small molecules at infection sites can influence antibiotic effectiveness and explores new targets for improving antibiotic treatments.

## Contribution

The paper highlights chemical-mediated resistance mechanisms and identifies potential new targets for antibiotic adjuvant development.

## Key findings

- Small molecules at infection sites can transiently alter bacterial responses to antibiotics.
- Chemicals produced by bacteria may offer communal protection against antibiotics.
- Genetically encoded mechanisms for chemical response could serve as new drug targets.

## 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.