Collateral sensitivity interactions between antibiotics depend on local abiotic conditions

Mutations conferring resistance to one antibiotic can increase (cross resistance) or decrease (collateral sensitivity) resistance to others. Drug combinations displaying collateral sensitivity could be used in treatments that slow resistance evolution. However, lab-to-clinic translation requires understanding whether collateral effects are robust across different environmental conditions. Here, we isolated and characterized resistant mutants of Escherichia coli using five antibiotics, before measuring collateral effects on resistance to other antibiotics. During both isolation and phenotyping, we varied conditions in ways relevant in nature (pH, temperature, bile). This revealed local abiotic conditions modified expression of resistance against both the antibiotic used during isolation and other antibiotics. Consequently, local conditions influenced collateral sensitivity in two ways: by favouring different sets of mutants (with different collateral sensitivities), and by modifying expression of collateral effects for individual mutants. These results place collateral sensitivity in the context of environmental variation, with important implications for translation to real-world applications.