Eradicating Bacterial Persisters with Combinations of Strongly and Weakly Metabolism-Dependent Antibiotics.

The vast majority of bactericidal antibiotics display poor efficacy against bacterial persisters, cells that are in a metabolically repressed state. Molecules that retain their bactericidal functions against such bacteria often display toxicity to human cells, which limits treatment options for infections caused by persisters. Here, we leverage insight into metabolism-dependent bactericidal antibiotic efficacy to design antibiotic combinations that sterilize both metabolically active and persister cells, while minimizing the antibiotic concentrations required. These rationally designed antibiotic combinations have the potential to improve treatments for chronic and recurrent infections. • Antibiotics are strongly or weakly dependent on metabolism (SDM or WDM) • Combinations of SDM and WDM antibiotics sterilize bacteria, while dose-sparing • SDM and WDM drug interactions are undetectable in growth-inhibition assays Zheng et al. rationally combine antibiotics using insights on bacterial metabolism to identify drug-drug combinations that sterilize bacterial cultures of both metabolically active and persister cells, while dose-sparing toxic antibiotics. [ABSTRACT FROM AUTHOR]