Chemical probes to modulate acyl-homoserine lactone quorum signal synthesis

调节酰基高丝氨酸内酯群体信号合成的化学探针

• 批准号: 10784999
• 负责人: Rajesh Nagarajan
• 金额: $ 9.47万
• 依托单位: BOISE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10784999
• 关键词: Acyl Coenzyme A; Applications Grants; Bacteria; Binding; Biomedical Research; Cell Communication; Cells; Chemicals; Coupling; Data; Environment; Enzymes; Foundations; Goals; Gram-Negative Bacteria; Home; Institution; Interruption; Physicians; Population Density; Pseudomonas aeruginosa; Research; S-Adenosylhomocysteine; S-Adenosylmethionine; Signal Transduction; Specificity; Virulence; analog; design; homoserine lactone; infection rate; inhibitor; multi-drug resistant pathogen; novel; programs; quorum sensing; rational design; small molecule; small molecule inhibitor; tool; undergraduate student

Abstract Gram-negative bacteria count specific, N-acyl-L-homoserine lactone (AHL) quorum sensing (QS) signals in the environment to estimate local population densities, facilitate cell-cell communication and virulence. AHL synthases make AHL autoinducer signals by enzymatically coupling acyl-ACP/acyl-CoA and S-adenosyl-L- methionine metabolites to facilitate quorum sensing for the bacterium. Small molecule inhibitors of AHL synthase enzymes would limit signal synthesis, interrupt quorum sensing and thus hold significant promise as chemical tools to investigate QS networks in bacteria. Designing AHL synthase-specific inhibitors, however, does remain a significant challenge. To develop AHL synthase selective inhibitors, we recently embarked on a proof-of-concept study to evaluate the potential of AHL signal derivatives as product analog inhibitors of Pseudomonas aeruginosa RhlI AHL synthase. In this study, we demonstrated that AHL analogs could serve as ‘chemical probes’ to uncover novel inhibition and activation binding pockets that could be tapped to develop potent AHL synthase-specific modulators. In this grant application, we extend this approach on a broader scale to evaluate the utility of AHL analog chemical probes in discovering novel binding pockets, determining the mechanistic basis of AHL synthase modulation, and formulating the rules of AHL engagement in short, medium and long-chain preferring AHL synthases. Additionally, we will determine how the inhibition and activation pockets could be leveraged to develop novel substrates and substrate analog inhibitors of AHL synthases. Successful completion of these studies should inform the rational design of inhibition and activation pocket directed AHL synthase modulators. Finally, the goals described in this application are tightly aligned with the objectives of AREA program, which are to a) support meritorious research at an undergraduate focused institution, b) strengthen the research environment at the home institution and c) provide opportunity for undergraduate students to get involved in biomedical research.

抽象的 革兰氏阴性菌计数特异性 N-酰基-L-高丝氨酸内酯 (AHL) 群体感应 (QS) 信号 环境来估计当地人口密度，促进细胞间通讯和 AHL 毒力。 合酶通过酶促偶联酰基-ACP/酰基-CoA 和 S-腺苷-L- 产生 AHL 自诱导信号 蛋氨酸代谢物促进细菌群体感应 AHL 小分子抑制剂。 合酶将限制信号合成，中断群体感应，因此具有重大前景 然而，作为研究细菌 QS 网络的化学工具，设计 AHL 合酶特异性抑制剂。 为了开发 AHL 合酶选择性抑制剂，我们最近着手进行。 一项概念验证研究，旨在评估 AHL 信号衍生物作为产品类似物抑制剂的潜力 铜绿假单胞菌 RhlI AHL 合酶 在这项研究中，我们证明了 AHL 类似物可以发挥作用。 作为“化学探针”来发现新的抑制和激活结合口袋，可以利用这些结合口袋来开发 有效的 AHL 合酶特异性调节剂 在本次拨款申请中，我们将这种方法扩展到更广泛的领域。 评估 AHL 模拟化学探针在发现新型结合袋、确定 AHL合酶调节的机制基础，并简要制定AHL参与规则， 此外，我们将确定如何抑制和抑制中链和长链的 AHL 合酶。 激活口袋可用于开发 AHL 的新型底物和底物类似物抑制剂 成功完成这些研究应该为抑制和激活的合理设计提供信息。 最后，本申请中描述的目标是紧密一致的。 AREA 计划的目标是：a) 支持本科生的优秀​​研究 重点机构，b) 加强母机构的研究环境，c) 提供机会 供本科生参与生物医学研究。