Unlocking the enigma of phenotypic drug tolerance: Mechanisms and emerging therapeutic strategies

In the ongoing battle against antimicrobial resistance, phenotypic drug tolerance poses a formidable challenge. This adaptive ability of microorganisms to withstand drug pressure without genetic alterations further complicating global healthcare challenges. Microbial populations employ an array of persistence mechanisms, including dormancy, biofilm formation, adaptation to intracellular environments, and the adoption of L-forms, to develop drug tolerance. Moreover, molecular mechanisms like toxin-antitoxin modules, oxidative stress responses, energy metabolism, and (p)ppGpp signaling contribute to this phenomenon. Understanding these persistence mechanisms is crucial for predicting drug efficacy, developing strategies for chronic bacterial infections, and exploring innovative therapies for refractory infections. In this comprehensive review, we dissect the intricacies of drug tolerance and persister formation, explore their role in acquired drug resistance, and highlight emerging therapeutic approaches to combat phenotypic drug tolerance. Furthermore, we outline the future landscape of interventions for persistent bacterial infections.