Mutation-based mechanisms of antibiotic resistance

SUMMARYAntibiotic resistance is a major global health threat, with an estimated 1.14 million deaths in 2021 linked to antibiotic resistance. Mutations naturally arise as bacteria evolve to defend against and survive various environmental challenges, including those exerted by antibiotics. Both overuse and misuse of antibiotics can accelerate selection for resistant bacteria. Misuse can happen when antibiotic treatment ends prematurely, resulting in sub-lethal antibiotic levels. This provides an ideal environment for the proliferation of resistance-causing mutations, which, in some cases, are enhanced further by triggering the synthesis of error-prone DNA polymerases. Low levels of antibiotics are also found in the environment, creating breeding grounds for the evolution of antibiotic resistance. Mutations diminish the impact of antibiotics by three principal mechanisms: (i) reducing antibiotic influx, (ii) elevating antibiotic efflux, and (iii) altering cellular targets of antibiotics. The first two mechanisms confer modest resistance against a broad range of antibiotics; however, in combination with the third target-specific mechanism, they become the foundation of high-level antibiotic resistance. Ultimately, while the manifestation of mutations cannot be prevented, steps can be taken to lower their frequency by carefully considering the need for antibiotic prescription, exploring combination therapies, integrating adjuvants such as efflux pump inhibitors, and minimizing environmental contamination of antibiotics.