Heteroresistance Interdisciplinary Research Unit

摘要 抗生素耐药性是我们这个时代最严重的医学挑战之一。这场危机使病人处于危险之中。 无法治愈的细菌感染，并威胁依赖抗生素的现代医学的重大进步 (移植、化疗等)。在中国，每年至少有280万例耐药感染 导致超过35,000人死亡[1]。如果不采取重大行动，由于这些原因，全球每年的死亡率 预计到2050年，感染人数将达到1000万，超过癌症的预测[2]。理解 耐药机制对于设计对抗耐药细菌的新方法和治疗方法至关重要。 异质性耐药(HR)是一种神秘的抗生素耐药性形式，其中细菌分离物含有 在抗生素存在的情况下可以快速复制的抗药性亚群，而敏感的 亚群被杀[3，4]。不仅许多种类的细菌表现出这种形式的表型耐药性， 但据报道，它几乎对所有类别的抗生素都有作用[3，5，6]。不幸的是，我们对 HR极其有限，其在感染期间的相关性尚不清楚。我们最近展示了人力资源 对于不同的抗生素，包括最后一线抗生素粘菌素，在体内模型中可能导致治疗失败[4， 5、7]。此外，当抗性亚群的频率非常低(10,000个细胞中有1个)时，HR是 被临床诊断测试错误归类为易感，但仍能调解治疗失败[4]。我们的 监测数据显示，即使在高度耐药的人群中，对不同类别抗生素的HR也很普遍 耐碳青霉烯类肠杆菌科(CRE)和鲍曼不动杆菌(螃蟹)。此外，我们最近 发现用两种抗生素靶向泛耐药细菌，一种菌株表现出HR可靠地导致 有效的联合治疗，强调人力资源知识可以用来指导有效的治疗 [5]。综上所述，这些数据突显了人力资源在很大程度上未被认识到和未被发现的流行病 可能导致不明原因的抗生素治疗失败，但也可以用于治疗的临床。 异质电阻跨学科研究单位(HR-IRU)汇集了一个跨学科团队 专家们做出了前所未有的努力，以了解人力资源的机制、动态和流行。这个 由临床隔离和单细胞分析核心支持的拟议项目将结合使用 遗传学、单细胞显微镜、动态血流和体内感染研究、建模和流行病学 分析以获得对人力资源的基础性见解。在基本层面上，这项工作将大大拓宽我们的 了解细胞亚群表现出的特征如何影响细菌生理学。在一次 翻译水平，这一努力将是我们对抗抗药性细菌的关键一步，并为 为发现新的疗法、诊断方法和减轻人类痛苦的方法奠定了基础。

ABSTRACT Antibiotic resistance is one of the most serious medical challenges of our time. This crisis puts patients at risk of untreatable bacterial infections and threatens major advances of modern medicine that rely on antibiotics (transplants, chemotherapy, etc). There are at least 2.8 million antibiotic resistant infections each year in the US, leading to over 35,000 deaths [1]. Without significant action, worldwide annual mortality due to these infections is predicted to reach 10 million by 2050, surpassing that predicted for cancer [2]. Understanding resistance mechanisms is critical to designing novel approaches and therapeutics to combat resistant bacteria. Heteroresistance (HR) is an enigmatic form of antibiotic resistance in which a bacterial isolate harbors a resistant subpopulation that can rapidly replicate in the presence of an antibiotic, while a susceptible subpopulation is killed [3, 4]. Not only do many species of bacteria exhibit this form of phenotypic resistance, but it has been reported against nearly all classes of antibiotics [3, 5, 6]. Unfortunately, our understanding of HR is extremely limited and its relevance during infection has been unclear. We recently demonstrated that HR to diverse antibiotics, including the last-line antibiotic colistin, can cause treatment failure in an in vivo model [4, 5, 7]. Furthermore, when the frequency of the resistant subpopulation is very low (<1 in 10,000 cells) HR is misclassified as susceptible by clinical diagnostic tests, yet is still able to mediate treatment failure [4]. Our surveillance data reveal that HR to diverse classes of antibiotics is widespread even among highly resistant carbapenem-resistant Enterobacteriaceae (CRE) and Acinetobacter baumannii (CRAB). Further, we recently discovered that targeting pan-resistant bacteria with two antibiotics to which a strain exhibits HR reliably leads to effective combination therapy, highlighting that knowledge of HR can be used to guide effective therapies [5]. Taken together, these data highlight a largely unappreciated and undetected epidemic of HR in the clinic that may cause unexplained antibiotic treatment failure but can also be exploited therapeutically. The Heteroresistance Interdisciplinary Research Unit (HR-IRU) brings together an interdisciplinary team of experts in an unprecedented effort to understand the mechanisms, dynamics, and prevalence of HR. The proposed projects, supported by Clinical Isolate and Single-Cell Analysis Cores, will use a combination of genetics, single cell microscopy, dynamic flow and in vivo infection studies, modeling, and epidemiological analyses to make foundational insights into HR. At a basic level, this work will significantly broaden our understanding of how traits exhibited by subpopulations of cells can impact bacterial physiology. At a translational level, this effort will be a critical step in our fight against antibiotic resistant bacteria and lay the foundation for the discovery of novel therapeutics, diagnostics, and approaches to alleviate human suffering.