Exploiting collateral sensitivity to combat antimicrobial resistance: Mechanisms and opportunities

Collateral sensitivity (CS) was first described by Szybalski and Bryson in 1952. It refers to the phenomenon where bacteria become more susceptible to one antibiotic when they develop resistance to another. Given the global rise of antimicrobial resistance (AMR) and advancements in next-generation sequencing and high-throughput experimental techniques, researchers aim to leverage CS to mitigate or even reverse the spread of AMR by elucidating the molecular mechanisms underlying CS. This paper reviews recent progress in CS research, focusing on laboratory methods, resistance mechanisms leading to CS, and the molecular characterization of CS across different bacterial species. Unlike previous overviews, this article synthesizes the intersection of experimental methodologies and molecular mechanisms to provide a cohesive framework for translating CS from evolutionary principles to clinical application. • Collateral sensitivity (CS) acts as an evolutionary trade-off mechanism to counter antimicrobial resistance (AMR). • This review discusses the advantages and disadvantages of experimental methods used to study drug resistance evolution, as well as the genetic and molecular mechanisms driving the evolution of CS. • CS molecular characterization across diverse bacterial species is detailed for clinical translation. • Leveraging CS knowledge offers a rational strategy for designing effective antibiotic cycling and combination therapy regimens.