Examining SecA as a Potential Target for Treating Gram-positive Bacteria

描述(申请人提供)：由于耐药性的广泛出现，由细菌病原体引起的疾病近年来已成为一个主要的公共卫生问题。迫切需要开发新的抗菌剂，特别是那些具有新靶点和/或能够克服耐药性的抗菌剂。该项目的长期目标是开发新型抗菌剂来抑制SECA，SECA是所有细菌中存在的蛋白质转运机制中不可或缺的ATPase。SECA负责分泌许多重要的蛋白质、重要的毒素和其他毒力因子，对细菌的生存至关重要。SECA在哺乳动物细胞中没有类似物，因此为开发抗菌剂提供了一个理想的靶点。我们假设，抑制这种必要的蛋白质将导致阻碍细菌的生长和/或生存。此外，SecA作为一种膜蛋白发挥作用，形成跨膜通道，从而为抗菌剂在不进入细胞的情况下达到这一目标提供了可能性。因此，这些抑制剂可能具有克服外排泵效应从而产生多药耐药(MDR)的内在能力。此外，由于SecA存在于所有细菌中，这是开发广谱抗菌剂的目标。事实上，我们的初步结果支持所有这些假设。在这个项目中，我们计划研究机制问题，目的是研究靶向SecA用于潜在抗菌剂开发的可行性。该项目基于强劲的初步结果，包括我们发现了非常有希望的抗菌剂，这些抗菌剂抑制了SecA，并在耐药细菌株上显示出比已知药物(如万古霉素)更有效的活性，以及一个有着长期合作历史的强大的研究团队。这项拟议研究的成功完成将为未来开发具有新作用机制并有可能克服外排介导的耐药性的新型抗菌剂奠定坚实的基础。

DESCRIPTION (provided by applicant): Due to the widespread emergence of drug-resistance, diseases caused by bacterial pathogens have become a major public health concern in recent years. There is an urgent need for the development of new antimicrobials, especially those that have a new target and/or can overcome drug resistance. The long-term goal of this project is the development of novel antimicrobial agents that inhibit SecA, an indispensable ATPase of the protein translocation machinery present in all bacteria. SecA is responsible for the secretion of many vital proteins, important toxins and other virulence factors, and is essential for bacterial survival. SecA has no counterpart in mammalian cells, thus providing an ideal target for developing antimicrobial agents. We hypothesize that inhibition of this essential protein would lead to hindered bacterial growth and/or viability. Moreover, SecA functions as a membrane protein, forming a transmembrane channel, and thus provides the possibility for antimicrobial agents to reach this target without entering into the cells. Therefore, these inhibitors may have the intrinsic ability to overcome the effect of efflux pumps and thus multi-drug resistance (MDR). In addition, because SecA is present in all bacteria, this is a target for the development of broad-spectrum antimicrobials. Indeed, our preliminary results support all these hypotheses. In this project, we plan to examine the mechanistic issues aimed at examining the feasibility of targeting SecA for the development of potential antimicrobial agents. The project is based on strong preliminary results including our finding of very promising antimicrobial agents that inhibit SecA and show more potent activities than known drugs such as vancomycin on drug resistant strains of bacteria, and a strong team of investigators that have had a long collaboration history. Successful completion of the proposed research will lay a strong foundation for future development of novel antimicrobials that have a new mechanism of action and have the potential to overcome efflux-mediated drug resistance.