Selection of resistance at lethal and non-lethal antibiotic concentrations

► The genetics of strong selections may be a misleading basis for understanding antibiotic resistance evolution in clinical settings. ► Antibiotic-resistance evolution at non-lethal concentrations of drug is likely to select high-frequency low-cost genetic alterations. ► High-resolution competition assays show that resistance mutations are enriched, and selected de novo, at very low antibiotic concentrations. ► Genomic analysis of resistant clinical isolates needs to be complemented with experimental evolution studies and genetic reconstructions. ► It is important to determine the functional significance of each individual mutation in the trajectory of resistance evolution.