Breaking biofilms: novel biofilm modifying enzymes from human skin bacteria to target Staphylococcus aureus infections

金黄色葡萄球菌（Staphylococcus aureus）是一种重要的人类致病菌，其耐甲氧西林菌株（Methicillin resistant strains，MRSA）每年导致超过10万人死亡。这种细菌与其他葡萄球菌一起生活在健康人的皮肤和鼻子上，通常通过皮肤损伤引发感染。因此，破坏皮肤的医疗程序，如导管和其他留置医疗器械是MRSA感染的重要医院途径。生物膜的形成对于定殖和感染的起始是必不可少的，生物膜基质通常由N-乙酰葡糖胺（PNAG）的聚合物组成。在研究葡萄球菌使用的PNAG的生物合成时，我们发现了存在于各种葡萄球菌的生物合成伊卡操纵子中的新基因，我们假设该基因具有PNAG切割活性（PNAGase）。我们认为这可以调节释放到细胞表面的PNAG聚合物的长度，直接影响生物膜特性和感染。在这个项目中，你将加入一个蓬勃发展的资金充足的小组在部门。她是约克大学的生物学教授，与糖生物学家、合成化学家和临床研究人员有着密切的联系。主要目的是采取微生物和生物化学相结合的方法来抑制新的PNAGase酶，使用生物技术设施中的先进显微镜技术确定PNAGase对细菌生物膜生产的影响，并研究从金黄色葡萄球菌致病菌株中去除此功能的影响。这将包括MRSA菌株，并将使用现代遗传技术进行基因灭活。这些目标将通过谢菲尔德大学葡萄球菌遗传学专家Rebecca科里根博士和船体约克医学院（HYMS）细菌生物膜功能专家Marjan货车der Woude教授的额外专业知识实现。最后，你有机会在沙门氏菌模型中测试新酶的治疗用途。金黄色葡萄球菌感染与临床同事在HYMS在船体大学。该项目的基础是在生物膜生物合成簇中发现新的酶，这些酶有可能改变生物膜的特性，并可能作为抗感染药物发挥重要作用。迫切需要新的治疗方法来对抗传染病，这个项目将把你放在这些努力的中心。如果你对细菌毒力有背景和兴趣，这个项目是理想的。生物化学和遗传学，并有兴趣致力于操纵病原体过程，以解决人类疾病。

Staphylococcus aureus is an important human bacterial pathogen with methicillin resistant strains (MRSA) causing over 100k deaths annually. The bacterium lives on the skin and nose of heathy humans, alongside other commensal Staphylococci, and usually initiates infections through skin damage. Hence, medical procedures that break the skin, such as catheters and other indwelling medical devices are an important nosocomial route of MRSA infections. The formation of a biofilm is essential for colonisation and initiation of infection, with the biofilm matrix usually composed of a polymer of N-acetylglucosamine (PNAG). While studying the biosynthesis of PNAG used by Staphylococci, we discovered a new gene present in the biosynthetic ica operons of various Staphylococci that we hypothesise has PNAG cleaving activity (PNAGase). This we think functions to regulate the length of PNAG polymers released onto the cell surface, directly impacting on biofilm properties and infection. In this project you will join a thriving well-funded group in the Dept. of Biology at the University of York with strong links to glycobiologists, synthetic chemists and clinical researchers. The primary aims are to take a combined microbiological and biochemical approach to characterise the new PNAGase enyzmes, determine the impact of PNAGase on biofilm production by bacteria using advanced microscopy techniques available in the Biology Technology Facility and investigate the impacts of removing this function from pathogenic strains of Staphylococcus aureus. This will include MRSA strains and will use modern genetic technique for gene inactivation. These aims will be enabled through the additional expertise of Dr. Rebecca Corrigan, who specialises in staphylococcal genetics at the University of Sheffield and Prof. Marjan van der Woude, an expert in bacterial biofilm function, in the Hull York Medical School (HYMS). Finally you have the opportunity to test the therapeutic use of the new enzymes in models of S. aureus infection with clinical colleagues at HYMS in the University of Hull. The project builds on the discovery of novel enzymes in biofilm biosynthetic clusters that have the potential to alter biofilm properties and could have important roles as anti-infectives. There is an urgent need for new therapeutics to combat infectious disease and this project will place you at the centre of these efforts. The project is ideal if you have a back ground and interests in bacterial virulence. Biochemistry and genetics, and are interested in working towards manipulating pathogen processes to address human disease.