Multidrug-resistant (MDR) bacteria and their rapid global spread has become one of the most significant challenges to the health of the population and has significantly weakened the efficacy of traditional antibiotic treatment, resulting in a high morbidity, mortality, and healthcare expenses. In spite of the fact that classical genetic mechanisms, including the target modification, the enzymatic drug deactivation, and the efflux pump overexpression, were known as the main causes of resistance, the mechanisms are not able to describe the complexity of the failure in antibiotic treatment which is observed in clinical practices. There is mounting evidence to support the idea that non-genetic adaptive strategies are important in the surviving of bacteria under antibacterial pressure. Here in this review, we give a critical overview of how epigenetic reprogramming and metabolic plasticity contribute to the selection of phenotypes that relate to multidrug resistance in bacteria. These mechanisms allow bacterial genome epigenetic regulation, such as DNA methylation, phase variation, and regulation by the nucleoid-associated protein, which is rapid and reversible and does not modify the underlying DNA sequence. The processes produce phenotypic heterogeneity in bacterial populations, which facilitates antibiotic tolerance, persistence and frequent infections. Simultaneously, metabolic plasticity enables MDR bacteria to be able to restructure metabolic pathways in real time, to enter low-energy or dormant states, and to evade antibiotic-directed processes, which increases the antibiotic resistance and survival chances. Notably, the arising crosstalk between epigenetic regulation and metabolic networks as the key axis of adaptation in MDR bacteria is emphasized in this review. The two-way communications among these two regulatory layers not only orchestrate stress responses, but also stabilize adaptive phenotypes, and also cause treatment failure in the absence of stable genetic resistance. We also explain the new molecular targets and intervention approaches to disrupt epigenetic and metabolic changes, such as epigenetic regulators, metabolic regulators and combination therapy to restore the activity of antibiotics. This review takes a systems view of multidrug resistance in bacteria by incorporating existing information on the topics of genetics, epigenetics, and metabolism. The comprehension of epigenetic reprogramming and metabolic plasticity interaction opens up new prospects of developing novel antimicrobial interventions that may overpower antibiotic treatment failure and solve the increasing global problem of the MDR bacterial infections.
Ali Hassanen Ali* (Sun,) studied this question.