Collateral Sensitivity Interactions between Antibiotics Depend on Local Abiotic Conditions

Abstract

When bacteria become resistant to an antibiotic, the genetic changes involved sometimes increase (cross-resistance) or decrease (collateral sensitivity) their resistance to other antibiotics. Antibiotic combinations showing repeatable collateral sensitivity could be used in treatment to slow resistance evolution. However, collateral sensitivity interactions may depend on the local environmental conditions that bacteria experience, potentially reducing repeatability and clinical application. Here, we show that variation in local conditions (pH, temperature, and bile salts) can influence collateral sensitivity in two ways: by favoring different sets of mutants during bacterial resistance evolution (with different collateral sensitivities to other antibiotics) and by modifying expression of collateral effects for individual mutants. This suggests that translation from the lab to the clinic of new approaches exploiting collateral sensitivity will be influenced by local abiotic conditions.