细菌药物耐受

Drug tolerance in bacteria

细菌药物耐受(Drug tolerance)是指在没有发生耐药突变的情况下细菌耐受抗生素杀菌的能力,表现为细菌群体难以或不能被杀菌型药物清除。细菌药物耐受的调控机制包括群体异质性和压力应答两种途径。药物耐受性的本质是细菌通过调控或遗传突变的方式改变生理代谢状态,从而抵制药物引起的细胞死亡途径。比如,处于缓慢生长或生长停滞生理状态的细菌往往能够抵抗药物的杀菌作用。临床研究发现细菌药物耐受是导致持续性感染疾病迁延难愈、复发率高的病原学机制之一。同时,研究证明耐受性的形成是细菌耐药性(Drug resistance)产生的进化途径之一。因此,揭示细菌药物耐受的机制将有助于人们深入了解抗生素的杀菌机理,以及细菌耐药性形成的适应性进化机制,并为新型杀菌药物以及药物增效剂靶标的发现和抗生素合理使用策略的开发奠定理论基础。

Drug tolerance is the capacity of genetically susceptible bacteria to survive the killing bybactericidal antibiotics.At population level,drug tolerance can result in slow killing kinetics or failure ofsterilization by antibiotic treatment.Drug tolerance can stem from phenotypic heterogeneity or fromenvironmentally induced stress response at population level.While various genes and pathways were shownto be implicated in bacterial drug tolerance,it is becoming clear that the common mechanism underlies thesurvival of antibiotic-tolerant cells is the alteration of cellular growth or metabolic state achieved by eitherregulation or genetic mutation,which counteracts or diminishes the killing effect induced by the drug-targetinteraction.Increasing clinic evidence shows that drug tolerance is a causative reason account for therequirement of lengthy treatment and the high relapse rate observed in persistent infections.Importantly,recent studies demonstrated that drug tolerance could accelerate the emergency of drug-resistant mutants.Therefore,deciphering the molecular mechanisms of antibiotic tolerance may shed light on ourunderstanding of antibiotic killing and the adaptive evolution of antibiotic resistance,and could facilitate thedevelopment of new intervention agents and therapeutic strategies.