Evolution of resistance to a tricyclic pyrimidoindole DNA gyrase/topoisomerase inhibitor in Escherichia coli and Acinetobacter baumannii is driven by upregulation of efflux machinery.

The significance of this work is in assessing the mutational landscape and evolutionary dynamics of resistance acquisition against a novel antibiotic, GP6. This approach showed that, in contrast to ciprofloxacin (CIP), a previously studied a canonical DNA gyrase/topoisomerase-targeting clinical antibiotic, evolution of GP6-resistance is driven largely by early and most prominent mutational events leading to upregulation of efflux machinery. An identified asymmetry in cross-resistance of evolved GP6- vs CIP-resistant clones provides important guidelines for rational selection of potential treatment regimens. This study illustrates the utility of the established morbidostat-based comparative resistomics workflow for the assessment of new drug candidates and clinical antibiotics.