Bacillithiol metabolism in Staphylococcus aureus

金黄色葡萄球菌中的杆菌硫醇代谢

• 批准号: 8268062
• 负责人: MAMTA RAWAT
• 金额: $ 10.38万
• 依托单位: CALIFORNIA STATE UNIVERSITY FRESNO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8268062
• 关键词: Acetyl Coenzyme A; Acetylcysteine; Acids; Actinobacteria class; Amides; Amidohydrolases; Anabolism; Antibiotic Resistance; Antibiotics; Bacillus (bacterium); Bacterial Infections; Biochemistry; Candidate Disease Gene; Cell physiology; Cells; Chiroptera; Cleaved cell; Community-Acquired Infections; Cyanobacterium; Cysteine; Deacetylase; Deacetylation; Development; Disease; Disulfides; Drug Delivery Systems; Drug Metabolic Detoxication; Drug resistance; Enzyme Tests; Enzymes; Equilibrium; Eukaryota; Glutathione; Goals; Gram-Negative Bacteria; Guanine + Cytosine Composition; Human; Infection; Infectious Skin Diseases; Inositol; Life; Ligation; Malates; Metabolism; Molecular Weight; Nosocomial Infections; Organism; Oxidation-Reduction; Oxidoreductase; Pathway interactions; Pharmaceutical Preparations; Phenotype; Play; Prevalence; Production; Reactive Nitrogen Species; Reactive Oxygen Species; Recombinant Proteins; Recombinants; Recycling; Research; Resistance; Septicemia; Source; Staphylococcal Infections; Staphylococcus aureus; Stress; Structure; Sulfhydryl Compounds; System; Therapeutic; Toxic Shock Syndrome; Toxin; Transferase; Vancomycin Resistance; Xenobiotics; amidase; coping; drug development; drug metabolism; enzyme activity; glycosyltransferase; human NAT2 protein; insight; methicillin resistant Staphylococcus aureus; mutant; pathogen

DESCRIPTION (provided by applicant): Methicillin resistant Staphylococcus aureus (MRSA) has become a serious source of life-threatening hospital infections and increasingly community acquired infections. As our current treatments for MRSA infections are losing efficacy, there is an urgent need for new antibiotics to cope with this problem. A recently discovered metabolite, bacillithiol (BSH), has been shown to be present in S. aureus and Bacillus spp., but is absent in human or other higher organisms. The specific aims of the research are to identify and characterize enzymes involved in BSH metabolism, such as bacillithiol disulfide reductase, and to elucidate S. aureus BSH dependent xenobiotic detoxification pathways. The results of these studies will elaborate the functions of BSH and will establish whether BSH metabolism is a suitable target for staphylococcal drug development. As thiols are known to be involved in the development of drug resistance, this research may provide insight into intrinsic drug resistance in S. aureus. PUBLIC HEALTH RELEVANCE: Staphylococcus aureus is a major human pathogen capable of causing a range of diseases from superficial skin infections to deadly septicemia and toxic shock syndrome. The increase in prevalence of methicillin resistant S. aureus (MRSA) strains and the advent of vancomycin resistant MRSA strains makes it imperative that new drug targets be identified and characterized. Drug detoxification and subsequent resistance pose serious problems to the further treatment of bacterial infections. Thiols have been shown to play a key role in detoxification and thus mechanisms of drug resistance and detoxification in S. aureus be carefully scrutinized in order to find ways to overcome these mechanisms. In this proposal, we identify and characterize potential new drug targets and explore the way S. aureus becomes resistant to existing drugs.

描述（由申请人提供）：耐甲氧西林金黄色葡萄球菌（MRSA）已成为危及生命的医院感染和越来越多的社区获得性感染的严重来源。由于我们目前对 MRSA 感染的治疗正在失去疗效，因此迫切需要新的抗生素来应对这一问题。最近发现的代谢物杆菌硫醇 (BSH) 已被证明存在于金黄色葡萄球菌和芽孢杆菌属中，但在人类或其他高等生物中不存在。该研究的具体目的是鉴定和表征 BSH 代谢中涉及的酶，例如杆菌硫醇二硫化物还原酶，并阐明金黄色葡萄球菌 BSH 依赖的异生物质解毒途径。这些研究的结果将详细阐述 BSH 的功能，并将确定 BSH 代谢是否是葡萄球菌药物开发的合适靶点。由于已知硫醇参与耐药性的发展，因此这项研究可以深入了解金黄色葡萄球菌的内在耐药性。 公共卫生相关性：金黄色葡萄球菌是一种主要的人类病原体，能够引起从浅表皮肤感染到致命败血症和中毒性休克综合症等一系列疾病。耐甲氧西林金黄色葡萄球菌 (MRSA) 菌株流行率的增加以及耐万古霉素 MRSA 菌株的出现使得新药物靶标的鉴定和表征势在必行。药物解毒和随后的耐药性给细菌感染的进一步治疗带来了严重问题。硫醇已被证明在解毒中发挥关键作用，因此需要仔细检查金黄色葡萄球菌的耐药性和解毒机制，以找到克服这些机制的方法。在本提案中，我们确定并描述了潜在的新药物靶点，并探索金黄色葡萄球菌对现有药物产生耐药性的方式。