Bacillithiol metabolism in Staphylococcus aureus

描述(申请人提供)：耐甲氧西林金黄色葡萄球菌(MRSA)已成为威胁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，迫切需要新的抗生素来应对这个问题。最近发现的一种代谢物，杆菌硫醇(BSH)，已被证明存在于金黄色葡萄球菌和芽孢杆菌中，但在人类或其他高等生物中不存在。本研究的具体目的是鉴定和鉴定与BSH代谢相关的酶，如杆菌硫醇二硫化物还原酶，并阐明依赖于BSH的金黄色葡萄球菌异源解毒途径。这些研究结果将阐明BSH的功能，并将确定BSH代谢是否适合葡萄球菌药物开发。由于硫醇已知参与耐药性的形成，这项研究可能为金黄色葡萄球菌的内在耐药性提供洞察力。 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，能够引起一系列疾病，从浅表皮肤感染到致命的败血症和中毒性休克综合征。随着耐甲氧西林金黄色葡萄球菌(MRSA)菌株的增多和对万古霉素耐药的MRSA菌株的出现，新的药物靶点的确定和表征势在必行。药物的脱毒和随后的耐药性给细菌感染的进一步治疗带来了严重的问题。硫醇已被证明在解毒中起关键作用，因此，为了找到克服这些机制的方法，必须仔细研究金黄色葡萄球菌的抗药性和解毒机制。在这项提案中，我们确定和表征了潜在的新药靶点，并探索了金黄色葡萄球菌对现有药物产生抗药性的方式。

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.