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到依赖抗生素的现代医学的重大进步 （移植、化疗等）。每年至少有280万例抗生素耐药性感染， 美国，导致超过35，000人死亡[1]。如果不采取重大行动， 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疗法至关重要。 异源耐药性（HR）是一种神秘的抗生素耐药性形式，其中细菌分离株携带一种 在抗生素存在下可以快速复制的耐药亚群，而敏感亚群可以在抗生素存在下快速复制。 亚群被杀[3，4]。不仅许多细菌物种表现出这种形式的表型抗性， 但据报道，它几乎对所有种类的抗生素都有效[3，5，6]。不幸的是，我们对 HR非常有限，其在感染期间的相关性尚不清楚。最近，我们发现HR 包括最后一种抗生素粘菌素在内的多种抗生素，可导致体内模型中的治疗失败[4， 5、7]。此外，当耐药亚群的频率非常低（<1/10，000个细胞）时，HR为 被临床诊断试验错误分类为易感，但仍能介导治疗失败[4]。我们 监测数据显示，即使在高度耐药的人群中， 碳青霉烯类耐药肠杆菌科（CRE）和鲍曼不动杆菌（CRAB）。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， 有效的联合治疗，强调HR的知识可用于指导有效的治疗 [5]的文件。总的来说，这些数据突出了一个在很大程度上未得到重视和未被发现的流行病的人力资源， 这可能导致无法解释的抗生素治疗失败，但也可以在治疗上加以利用。 异源抗性跨学科研究单位（HR-IRU）汇集了一个跨学科的团队， 专家在前所未有的努力，了解机制，动态，和流行的人力资源。 由临床分离株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、动态流动和体内感染研究、建模和流行病学 分析，使人力资源的基本见解。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性状如何影响细菌生理学。在 翻译水平，这一努力将是我们对抗抗生素耐药性细菌的关键一步， 基金会发现新的疗法，诊断和方法，以减轻人类的痛苦。

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.