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Acyl-homoserine lactone signal fidelity enforcing mechanism in bacterial communication

细菌通讯中酰基高丝氨酸内酯信号保真度执行机制

基本信息

批准号：
9012889
负责人：
Rajesh Nagarajan
金额：
$ 39.58万
依托单位：
BOISE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-01 至 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9012889
关键词：
Academic Research Enhancement Awards Acyl Carrier Protein Acyl Coenzyme A Acylation Address Affect Anti-Bacterial Agents Bacteria Bacterial Infections Binding Biomedical Research Burkholderia mallei Chemicals Chemistry Communication Complex Data Drug resistance Ensure Environment Enzymes Goals Gram-Negative Bacteria Infection Kinetics Lactones Mediating Methionine Microbial Biofilms Molecular Multi-Drug Resistance Outcome Physicians Physiological Play Population Density Process Product R Production Research Signal Transduction Social Behavior Students Testing Therapeutic Toxin United States National Institutes of Health Virulence analog antimicrobial base career combat design enzyme substrate complex homoserine lactone inhibitor/antagonist insight microbial multi-drug resistant pathogen non-Native novel public health relevance quorum sensing small molecule small molecule inhibitor tool

项目摘要

DESCRIPTION (provided by applicant): Infections caused by multidrug resistant organisms pose special challenges to treating bacterial infections and therefore therapeutic strategies that combat bacterial virulence without aggravating drug resistance are in great demand. Gram-negative bacteria use acyl- homoserine lactone mediated quorum sensing to regulate key physiological activities that includes virulence, biofilm formation and toxin production. Bacterial AHL synthases use acyl- ACP and S-adenosyl-L- methionine to make intracellular AHL autoinducer signals. Although small molecule inhibitors for AHL synthase enzymes hold significant promise as antimicrobials in treating multidrug resistant bacterial infections, designig AHL synthase specific inhibitors does remain a significant challenge because both acyl-ACP and SAM are used as substrates by many essential eukaryotic enzymes. To ensure efficient interbacterial communication, signal-synthesizing enzymes such as AHL synthases must precisely make the native signal for that bacterium and avoid synthesizing nonspecific signals (signal fidelity). In this proposal, we will investigate how AHL synthase enzymes selectively recognize their native acyl-substrate from a pool of non-native substrates to enforce signal fidelity in bacterial quorum sensing. In particular, we will determine the extent to which each enzymatic step in AHL synthesis contributes to signal fidelity. Based on our preliminary data with Burkholderia mallei BmaI1 AHL synthase, we hypothesize that acyl-substrate recognition predominantly occurs at [Enzyme.acyl-substrate.SAM] ternary complex. We will test this hypothesis for a broad array of AHL synthase enzymes. The three aims proposed in this application should collectively provide key insights into molecular basis of acyl-ACP substrate recognition by short, medium and long-chain synthases, which will inform the design of AHL synthase specific inhibitors.

描述(申请人提供)：由多重耐药生物引起的感染对治疗细菌感染提出了特殊的挑战，因此非常需要在不加剧耐药性的情况下对抗细菌毒力的治疗策略。革兰氏阴性菌利用酰基高丝氨酸内酯介导的群体感应来调节关键的生理活动，包括毒力、生物膜形成和毒素产生。细菌 AHL合成酶利用酰基-酸性磷酸酶和S-腺苷-L-蛋氨酸产生细胞内AHL自身诱导信号。尽管AHL合成酶的小分子抑制剂在治疗多药耐药细菌感染方面有很大的前景，但设计AHL合成酶特异性抑制剂仍然是一个巨大的挑战，因为许多重要的真核酶都使用酰基-ACP和SAM作为底物。为了确保有效的细菌间交流，信号合成酶，如AHL合成酶，必须准确地为该细菌产生天然信号，并避免合成非特定信号(信号保真度)。在这项提案中，我们将研究AHL合成酶如何从非天然底物池中选择性地识别其天然酰基底物，以加强细菌群体感应中的信号保真度。特别是，我们将确定AHL合成中的每个酶步骤对信号保真度的贡献程度。基于我们对Burkholderia Mallei BmaI1 AHL合成酶的初步数据，我们假设酰基底物识别主要发生在[Enzyme.acyl-substrate.SAM]三元复合体上。我们将在一系列广泛的AHL合成酶中检验这一假设。本申请中提出的三个目标将共同为短链、中链和长链合酶识别酰基-ACP底物的分子基础提供关键的见解，这将为AHL合酶特异性抑制剂的设计提供信息。