Bacterial heterogeneity and antibiotic persistence: bacterial mechanisms utilized in the host environment

Antibiotic persistence, or the ability of small subsets of bacteria to survive prolonged antibiotic treatment, is an underappreciated cause of antibiotic treatment failure. Over the past decade, researchers have discovered multiple different stress responses and mechanisms that can promote antibiotic persistence. However, many of these studies have been completed in culture-based systems that fail to truly replicate the complexities of the host environment, and it is unclear whether the mechanisms defined in in vitro studies are applicable during host infection. In this review, we focus our discussion on recent studies that utilize a mixture of ex vivo culture systems and animal models to understand what stressors in the host environment are important for inducing antibiotic persistence. Different host stressors are involved depending on the anatomical niche the bacteria reside in and whether the host immune system is primed to generate a more robust response against bacteria, which can result in differing downstream effects on antibiotic susceptibility. Bacterial pathogens can also utilize specific strategies to reprogram their metabolism, which is vital for transitioning into an antibiotic-persistent state within host tissues. Importantly, we highlight that more attention is needed to establish guidelines for in vivo work on antibiotic persistence, particularly when identifying antibiotic-persistent subpopulations and distinguishing these phenotypes from antibiotic tolerance. Studying antibiotic persistence in the context of the host environment will be crucial for developing tools and strategies to target antibiotic-persistent bacteria and increase the efficacy of antibiotic treatment.