Development of antibacterial compounds that block evolutionary pathways to resistance

TL;DR

This study combines computational and experimental methods to discover a novel antibacterial compound, CD15-3, that inhibits both wild-type and resistant E. coli DHFR, delaying resistance development and blocking evolutionary escape routes.

Contribution

The paper introduces a new compound, CD15-3, that effectively inhibits both WT and resistant DHFR, demonstrating a strategy to develop evolution drugs that prevent resistance.

Findings

CD15-3 inhibits WT and resistant DHFR with IC50 50-75 micromoles.

Resistance to CD15-3 is delayed compared to TMP.

Resistance involves efflux pump gene duplication, not target mutation.

Abstract

Antibiotic resistance is a worldwide challenge. A potential approach to block resistance is to simultaneously inhibit WT and known escape variants of the target bacterial protein. Here we applied an integrated computational and experimental approach to discover compounds that inhibit both WT and trimethoprim (TMP) resistant mutants of E. coli dihydrofolate reductase (DHFR). We identified a novel compound (CD15-3) that inhibits WT DHFR and its TMP resistant variants L28R, P21L and A26T with IC50 50-75 micromoles against WT and TMP-resistant strains. Resistance to CD15-3 was dramatically delayed compared to TMP in in vitro evolution. Whole genome sequencing of CD15-3 resistant strains showed no mutations in the target folA locus. Rather, gene duplication of several efflux pumps gave rise to weak (about twofold increase in IC50) resistance against CD15-3. Altogether, our results demonstrate the promise of strategy to develop evolution drugs - compounds which block evolutionary escape routes in pathogens.