ABSTRACT

Persistence has been linked to treatment failure since its discovery over 70 years ago and understanding formation, nature and survival of this key antibiotic refractory subpopulation is crucial to enhancing treatment success and combatting the threat of antimicrobial resistance (AMR). The term ‘persistence’ is often used interchangeably with other terms such as tolerance or dormancy. In this review we focus on ‘antibiotic persistence’ which we broadly define as a feature of a subpopulation of bacterial cells that possesses the non-heritable character of surviving exposure to one or more antibiotics; and persisters as cells that possess this characteristic. We discuss novel molecular mechanisms involved in persister cell formation, as well as environmental factors which can contribute to increased antibiotic persistence in vivo, highlighting recent developments advanced by single-cell studies. We also aim to provide a comprehensive model of persistence, the ‘hunker’ theory which is grounded in intrinsic heterogeneity of bacterial populations and a myriad of ‘hunkering down’ mechanisms which can contribute to antibiotic survival of the persister subpopulation. Finally, we discuss antibiotic persistence as a ‘stepping-stone’ to AMR and stress the urgent need to develop effective anti-persister treatment regimes to treat this highly clinically relevant bacterial sub-population.

中文翻译：

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持久性的表型异质性：一种新颖的持久性“Hunker”理论

 抽象的

自 70 多年前发现以来，耐药性一直与治疗失败有关，了解这一关键抗生素耐药亚群的形成、性质和生存对于提高治疗成功率和应对抗菌素耐药性 (AMR) 的威胁至关重要。术语“持久性”通常与其他术语（例如耐受性或休眠性）互换使用。在这篇综述中，我们重点关注“抗生素持久性”，我们将其广泛定义为细菌细胞亚群的一个特征，该亚群具有在接触一种或多种抗生素后仍能存活的非遗传特征；并作为具有这种特性的细胞持续存在。我们讨论了与持久细胞形成有关的新分子机制，以及有助于增加抗生素体内持久性的环境因素，强调了单细胞研究的最新进展。我们还旨在提供一个全面的持久性模型，即基于细菌群体内在异质性的“蹲伏”理论和无数有助于持久性亚群抗生素存活的“蹲伏”机制。最后，我们讨论了抗生素持久性作为 AMR 的“垫脚石”，并强调迫切需要开发有效的抗持久性治疗方案来治疗这种与临床高度相关的细菌亚群。