Understanding how adaptation to a given antibiotic increases the sensitivity to other antibiotics is of great medical importance for the understanding of evolutionary trade-offs. Here, the first experimental map of such collateral sensitivity is presented, along with insights into the underlying mechanisms.

Understanding how evolution of antimicrobial resistance increases resistance to other drugs is a challenge of profound importance. By combining experimental evolution and genome sequencing of 63 laboratory-evolved lines, we charted a map of cross-resistance interactions between antibiotics in Escherichia coli, and explored the driving evolutionary principles. Here, we show that (1) convergent molecular evolution is prevalent across antibiotic treatments, (2) resistance conferring mutations simultaneously enhance sensitivity to many other drugs and (3) 27% of the accumulated mutations generate proteins with compromised activities, suggesting that antibiotic adaptation can partly be achieved without gain of novel function. By using knowledge on antibiotic properties, we examined the determinants of cross-resistance and identified chemogenomic profile similarity between antibiotics as the strongest predictor. In contrast, cross-resistance between two antibiotics is independent of whether they show synergistic effects in combination. These results have important implications on the development of novel antimicrobial strategies.

The Genomic Landscape of Compensatory Evolution Laboratory selection experiment explains how organisms compensate for the loss of genes during evolution, and reveals the deleterious side-effects of this process when adapting to novel environments.