Adaptation and compensation in a bacterial gene regulatory network evolving under antibiotic selection

In this study, we discover that the early evolutionary response ofEscherichia coli to the antibiotic trimethoprim involves derepression of PhoPQ signaling, an Mg2+-sensitive two-component system, by inactivation of the MgrB feedback-regulatory protein. We report that derepression of PhoPQ confers trimethoprim-tolerance toE. coli by hitherto unrecognized transcriptional upregulation of dihydrofolate reductase (DHFR), target of trimethoprim. As a result, mutations inmgrB precede and facilitate the evolution of drug resistance. Using laboratory evolution, genome sequencing, and mutation re-construction, we show that populations ofE. coli challenged with trimethoprim are faced with the evolutionary ‘choice’ of transitioning from tolerant to resistant by mutations in DHFR, or compensating for the fitness costs of PhoPQ derepression by inactivating the RpoS sigma factor, itself a PhoPQ-target. Outcomes at this evolutionary branch-point are determined by the strength of antibiotic selection, such that high pressures favor resistance, while low pressures favor cost compensation. Our results relate evolutionary changes in bacterial gene regulatory networks to strength of selection and provide mechanistic evidence to substantiate this link.
Source: eLife - Category: Biomedical Science Tags: Genetics and Genomics Microbiology and Infectious Disease Source Type: research