By acquiring or evolving resistance to one antibiotic, bacteria can become cross-resistant to a second antibiotic, which further limits therapeutic choices. In the opposite scenario, initial resistance leads to collateral sensitivity to a second antibiotic, which can inform cycling or combinatorial treatments. Despite their clinical relevance, our knowledge of both interactions is limited. We used published chemical genetics data of the Escherichia coli single-gene deletion library in 40 antibiotics and devised a metric that discriminates between known cross-resistance and collateral-sensitivity antibiotic interactions. Thereby we inferred 404 cases of cross-resistance and 267 of collateral-sensitivity, expanding the number of known interactions by over threefold. We further validated 64/70 inferred interactions using experimental evolution. By identifying mutants driving these interactions in chemical genetics, we demonstrated that a drug pair can exhibit both interactions depending on the resistance mechanism. Finally, we applied collateral-sensitive drug pairs in combination to reduce antibiotic-resistance development in vitro.

通过获得或进化对一种抗生素的耐药性，细菌可以对第二种抗生素产生交叉耐药性，这进一步限制了治疗选择。在相反的情况下，初始耐药性导致对第二种抗生素的附带敏感性，这可以为循环或组合治疗提供信息。尽管它们具有临床相关性，但我们对这两种相互作用的了解是有限的。我们使用了 40 种抗生素中大肠杆菌单基因缺失文库的已发表化学遗传学数据，并设计了一个指标来区分已知的交叉耐药性和侧敏感抗生素相互作用。因此，我们推断出 404 例交叉耐药和 267 例附带敏感性，将已知相互作用的数量扩大了三倍以上。我们进一步验证了使用实验进化的 64/70 推断的相互作用。通过在化学遗传学中鉴定驱动这些相互作用的突变体，我们证明了药物对可以根据耐药机制表现出两种相互作用。最后，我们联合应用侧支敏感药物对以减少体外抗生素耐药性的发展。