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Selective modulation of bacterial chaperonins by targeting novel small molecule binding sites

通过靶向新的小分子结合位点选择性调节细菌伴侣蛋白

基本信息

批准号：
9889963
负责人：
Steven Michael Johnson
金额：
$ 43.41万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-05-01 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9889963
关键词：
Acinetobacter baumannii Anti-Bacterial Agents Antibiotic Resistance Antibiotics Bacteria Bacterial Antibiotic Resistance Bacterial Infections Binding Binding Sites Biochemical Biological Biophysics Cells Centers for Disease Control and Prevention (U.S.)Characteristics Communicable Diseases Complex Data Development Distal ESKAPE pathogens Enterobacter Enterococcus faecium Escherichia coli Exhibits Future Goals Human In Vitro Incidence Infection Infectious Agent Klebsiella pneumoniae Laboratories Lead Literature Mediating Medical Care Costs Mitochondria Molecular Molecular Conformation Molecular Machines Molecular Probes Morbidity - disease rate Multiple Bacterial Drug Resistance Nucleotides Pathway interactions Peptides Pharmaceutical Preparations Process Program Development Proteins Pseudomonas aeruginosa Research Resistance Risk Series Site Staphylococcus aureus Structure Superbug System Tissues Toxic effect Translating Treatment Efficacy United States X-Ray Crystallography antibiotic resistant infections bactericide base biophysical analysis chaperonin combat drug development drug resistant pathogen experimental study functional loss high throughput screening inhibitor/antagonist innovation lead candidate mortality mutant novel novel therapeutics outcome forecast proteostasis recruit scaffold side effect small molecule small molecule inhibitor societal costs

项目摘要

PROJECT SUMMARY: The growing incidences of antibiotic resistance is epitomized by the emergence of six multi-drug resistant bacteria referred to as the “ESKAPE” pathogens: Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species. Without research to develop new antibiotics that are effective against these drug resistant pathogens, we risk regressing to a pre-antibiotic era where infections were a leading cause of morbidity and mortality. To counter this threat, the long-term goal of this research is to develop new antibiotics that function by targeting bacterial GroEL chaperonin systems. GroEL is a centralized molecular machine that maintains the proper structure and function of hundreds of other proteins. Thus, targeting this one molecular machine will have the cascading effect of inhibiting hundreds of proteins at once, the functional losses of which bacteria will not be able to recover from. A caveat to this strategy is that human cells have a mitochondrial counterpart, called HSP60, and there remains the possibility of inhibitor cross-talk that could lead to toxic effects on host tissues. The central hypothesis is that the structural and functional divergence between bacterial and mammalian chaperonins, as well as other mammalian proteins, will allow the selective targeting of small molecule inhibitors for GroEL and bacteria without toxic side effects to human cells. This hypothesis has been formulated on the basis of well-established findings on chaperonin structure and function presented in the literature, and preliminary data for chaperonin inhibitors produced in the applicants' laboratories. In particular, human HSP60 functions as a single-ring oligomer, which removes many of the allosteric transitions that regulate the function of double-ring bacterial GroEL. In addition, preliminary data suggest there are multiple distinct binding sites on bacterial GroEL that compounds can interact with to block chaperonin function. Thus, the possibility of small molecules targeting these unique binding sites to selectively inhibit bacterial GroEL over HSP60 and other human proteins is high. The overall objective of this proposal is to identify these unique allosteric binding sites, elucidate the structural/functional mechanisms of action for molecules binding to these sites, and define the selectivity profiles for site-specific inhibitors in vitro and in cells. The rationale for the proposed studies is that delineating the precise structural/functional mechanisms of action of chaperonin inhibitors will permit the rational development GroEL-targeting antibiotic candidates. The approach is innovative because it proposes a unique and unexplored strategy of exploiting proteostasis machinery – specifically GroEL chaperonins – for killing infectious bacteria. Without a fundamental shift in strategy for treating infectious diseases, antibiotic resistance will continue to rise and the prognosis for surviving infection by these superbugs will continue to worsen. Therefore, the proposed studies will have significant impact because the research findings will open novel therapeutic strategies for a broad range of intractable infectious diseases.

项目摘要：六种抗生素耐药性的出现集中体现了抗生素耐药性发生率的不断上升多重耐药菌，称为“ESKAPE”病原体：屎肠球菌、葡萄球菌金黄色葡萄球菌、肺炎克雷伯菌、鲍曼不动杆菌、铜绿假单胞菌和肠杆菌物种。如果没有研究开发出有效对抗这些耐药病原体的新抗生素，我们面临着倒退回抗生素时代之前的风险，在这个时代，感染是发病和死亡的主要原因。到为了应对这一威胁，这项研究的长期目标是开发通过靶向作用发挥作用的新抗生素细菌 GroEL 伴侣蛋白系统。 GroEL 是一种集中式分子机器，可维持适当的数百种其他蛋白质的结构和功能。因此，针对这一分子机器将具有同时抑制数百种蛋白质的级联效应，而细菌的功能损失不会受到影响能够从中恢复。这一策略的一个警告是，人类细胞有一个线粒体对应物，称为 HSP60，并且仍然存在抑制剂串扰的可能性，这可能导致对宿主组织的毒性作用。中心假设是细菌和哺乳动物之间的结构和功能差异伴侣蛋白以及其他哺乳动物蛋白将允许选择性靶向小分子抑制剂用于GroEL和细菌，对人体细胞无毒副作用。这一假设是基于文献中提出的关于伴侣蛋白结构和功能的既定研究结果的基础，以及申请人实验室生产的伴侣蛋白抑制剂的初步数据。特别是，人类 HSP60 作为单环寡聚物发挥作用，消除了许多调节功能的变构转变双环细菌 GroEL。此外，初步数据表明有多个不同的结合位点化合物可以与细菌 GroEL 相互作用以阻断伴侣蛋白功能。因此，可能性很小靶向这些独特结合位点的分子可选择性抑制细菌 GroEL，而不是 HSP60 和其他细菌人体蛋白质含量很高。该提案的总体目标是确定这些独特的变构结合位点，阐明分子与这些位点结合的结构/功能作用机制，并定义体外和细胞内位点特异性抑制剂的选择性概况。拟议研究的理由是描述伴侣蛋白抑制剂的精确结构/功能机制将允许合理开发GroEL靶向抗生素候选药物。该方法具有创新性，因为它提出了利用蛋白质稳态机制（特别是 GroEL 伴侣蛋白）进行杀伤的独特且未经探索的策略传染性细菌。如果不从根本上改变治疗传染病的策略，抗生素耐药性就会出现将会继续上升，而这些超级细菌感染后存活下来的预后将继续恶化。因此，拟议的研究将产生重大影响，因为研究结果将开启新的篇章多种难治性传染病的治疗策略。