Impact of Host and Bacterial Metabolism on Antibiotic Susceptibility

Antimicrobial resistance (AMR) is a global healthcare emergency, directly causing 1.3 million deaths per year and predicted to increase dramatically over the coming decades. Understanding the molecular mechanisms underpinning antibiotic resistance is central to approaches for AMR surveillance and diagnosis in a clinical laboratory. Current antibiotic susceptibility tests are designed to detect canonical mechanisms of AMR that are functional on standard laboratory media. However, increasing evidence suggests that host and environmental factors can influence antibiotic susceptibility. In this perspective, we review known condition-dependent mechanisms of AMR and define them into four mechanistic classes: (1) Regulation of canonical AMR mechanisms by the host environment; (2) Changes to cellular respiration; (3) Increased metabolic capability; and (4) Metabolic control of tolerance and persistence. We further explore how these noncanonical AMR mechanisms can impact antibiotic susceptibility test results, and how increased mechanistic understanding might be used to optimize antibiotic therapy.