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

检查 SecA 作为治疗革兰氏阳性菌的潜在靶点

• 批准号: 8913328
• 负责人: ZEHAVA EICHENBAUM
• 金额: $ 44.4万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-22 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8913328
• 关键词: ATP phosphohydrolase; Address; Animal Model; Animals; Antimicrobial Effect; Attenuated; Bacteria; Bacterial Infections; Biological Assay; Cells; Collaborations; Cytoplasm; Development; Disease; Drug resistance; Effectiveness; Enzymes; Escherichia coli; Evaluation; Foundations; Future; Goals; Gram-Positive Bacteria; Growth; Health; Infection; Inhibitory Concentration 50; Kinetics; Lead; Mammalian Cell; Mediating; Membrane; Membrane Proteins; Metabolic; Modeling; Multi-Drug Resistance; Organism; P-Glycoprotein; Pharmaceutical Preparations; Pharmacologic Substance; Plant Roots; Property; Protein translocation; Proteins; Public Health; Publishing; Pump; Recording of previous events; Relative (related person); Research; Research Personnel; Resistance development; Role; Site; Staphylococcus aureus; Streptococcus pyogenes; Substrate Specificity; Testing; Toxin; Validation; Vancomycin; Virulence; Virulence Factors; Work; antimicrobial; antimicrobial drug; bactericide; base; drug resistant bacteria; efflux pump; in vitro Assay; inhibitor/antagonist; interest; killings; novel; pathogen; prevent; resistant strain

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.

描述（申请人提供）：由于耐药性的广泛出现，近年来由细菌病原体引起的疾病已成为主要的公共卫生问题。迫切需要开发新的抗微生物剂，特别是具有新靶点和/或可以克服耐药性的抗微生物剂。该项目的长期目标是开发抑制SecA的新型抗菌剂，SecA是所有细菌中蛋白质易位机制不可或缺的ATP酶。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，并且对细菌的生存至关重要。SecA在哺乳动物细胞中没有对应物，因此为开发抗微生物剂提供了理想的靶标。我们假设抑制这种必需蛋白质会导致细菌生长和/或活力受阻。此外，SecA作为膜蛋白发挥作用，形成跨膜通道，从而为抗菌剂提供了在不进入细胞的情况下到达该靶标的可能性。因此，这些抑制剂可能具有克服外排泵效应的内在能力，从而产生多药耐药（MDR）。此外，由于SecA存在于所有细菌中，因此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，旨在研究针对SecA开发潜在抗菌剂的可行性。该项目基于强有力的初步结果，包括我们发现了非常有前途的抗菌药物，这些抗菌药物抑制SecA，并显示出比已知药物（如万古霉素）对耐药菌株更有效的活性，以及一支拥有长期合作历史的强大研究团队。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药物奠定坚实的基础。

项目成果

Using Chemical Probes to Assess the Feasibility of Targeting SecA for Developing Antimicrobial Agents against Gram-Negative Bacteria.

使用化学探针评估以 SecA 为靶点开发针对革兰氏阴性菌的抗菌剂的可行性。

• DOI: 10.1002/cmdc.201600421
• 发表时间: 2016
• 期刊: ChemMedChem
• 影响因子: 3.4
• 作者: Jin,Jinshan;Hsieh,Ying-Hsin;Cui,Jianmei;Damera,Krishna;Dai,Chaofeng;Chaudhary,ArpanaS;Zhang,Hao;Yang,Hsiuchin;Cao,Nannan;Jiang,Chun;Vaara,Martti;Wang,Binghe;Tai,PhangC
• 通讯作者: Tai,PhangC

Evaluation of small molecule SecA inhibitors against methicillin-resistant Staphylococcus aureus.

• DOI: 10.1016/j.bmc.2015.09.027
• 发表时间: 2015-11-01
• 期刊: Bioorganic & medicinal chemistry
• 影响因子: 3.5
• 作者: Jin J;Cui J;Chaudhary AS;Hsieh YH;Damera K;Zhang H;Yang H;Wang B;Tai PC
• 通讯作者: Tai PC

Design, Synthesis and Evaluation of Triazole-Pyrimidine Analogues as SecA Inhibitors.

• DOI: 10.1002/cmdc.201500447
• 发表时间: 2016-01-05
• 期刊: ChemMedChem
• 影响因子: 3.4
• 作者: Cui J;Jin J;Chaudhary AS;Hsieh YH;Zhang H;Dai C;Damera K;Chen W;Tai PC;Wang B
• 通讯作者: Wang B

SecA: a potential antimicrobial target.

• DOI: 10.4155/fmc.15.42
• 发表时间: 2015
• 期刊: Future medicinal chemistry
• 影响因子: 4.2
• 作者: Chaudhary AS;Chen W;Jin J;Tai PC;Wang B
• 通讯作者: Wang B