Meeting gene expression demand during evolution of antibiotic resistance

Regulated gene expression in bacteria accommodates demands imposed by different environments. In addition to ensuring the production of required metabolic and structural components, gene regulation protects bacteria against the adverse effects of misexpression. Upon encountering a novel environment, such as sustained exposure to antibiotics, transcriptional recalibration ensues to improve fitness. For antibiotics, this involves enhancing the expression of an existing repertoire of resistance mechanisms and is often mediated by mutations in regulators of gene expression. Here, we review how diverse gene regulatory mutations confer antibiotic resistance to bacterial pathogens. We view these strategies through the lens of the Gene Expression Demand Theory, originally proposed for inducible operons involved in sugar metabolism, and describe the molecular basis and evolutionary consequences for a few well-studied examples. Broad underlying preferences of when and which kind of regulatory mutations bacteria employ emerge from these examples. A key pattern appears to be a preference for derepression rather than activating mutations, and we highlight potential underlying genetic and evolutionary explanations. Finally, even as our knowledge of molecular mechanisms of antibiotic adaptation continues to expand, we propose that adaptation by regulatory mutations provides a framework for assessing the risk of resistance evolution in the case of novel antibiotics and alternative targets for diagnostic and therapeutic interventions.