Allele-specific collateral and fitness effects determine the dynamics of fluoroquinolone resistance evolution

Abstract

Significance A promising strategy to overcome the evolution of antibiotic-resistant bacteria is to use collateral sensitivity-informed antibiotic treatments that rely on cycling or mixing of antibiotics, such that that resistance toward one antibiotic confers increased sensitivity to the other. Here, focusing on multistep fluoroquinolone resistance in Streptococcus pneumoniae , we show that antibiotic resistance induces diverse collateral responses whose magnitude and direction are determined by allelic identity. Using mathematical simulations, we show that these effects can be exploited via combination treatment regimens to suppress the de novo emergence of resistance during treatment.