Targeting and Containing the Spread of VRSA

项目总结(见说明)： 耐多药金黄色葡萄球菌(如耐甲氧西林金黄色葡萄球菌)和肠球菌(如万古霉素耐药肠球菌)出现在20世纪60年代的S和80年代的S，是医院-最近在社区-威胁生命的感染的主要原因。关键的是，经过20年的遏制，万古霉素耐药性从VRE转移到MRSA，产生了VRSA，现在有10个有充分记录的病例。该计划项目的总体目标是确定和开发治疗由VRSA和VRE引起的感染的新药。这将与研究携手进行，以了解该子项目所针对的多药耐药微生物的耐药性的发展和扩散。 总体目标：通过发现和检查，确定哪些遗传或生物事件导致VRE中万古霉素耐药性的破坏，并转移到VRSA，并展示新化合物对它们的活性： -已知的遗传事件(携带分离后杀死TA模块的质粒插入失活)， -10个有充分记录的VRSA毒株基因组中的未知特征，以及推定的 VRE捐赠者与他们隔绝， -遗传和代谢兼容性，这可能使它们在混合感染中共存或参与万古霉素耐药性转移，以及 -PPG中开发的化合物对这些高度耐多药的医院适应菌株的疗效 通过了解传播的基础以及这些日益耐药的菌株的性质，我们将更好地评估美国医院和社区感染的主要原因的抗生素敏感性持续侵蚀的威胁，并将对促进这种传播的条件类型保持警惕。

PROJECT SUMMARY (See Instructions): Multidrug resistant Staphylococcus aureus (e.g., methicillin resistant [MRSA]) and enterococci (e.g., vancomycin resistant [VRE]) emerged in the 1960's and 1980's, and are leading causes of life-threatening infection in the hospital - more recently also in the community. Critically, after 20 years of containment, vancomycin resistance moved from VRE to MRSA, creating VRSA, and there are now 10 well documented cases. The overall goal of this program project is to identify and develop new drugs for treating infections caused by VRSA and VRE. This will be conducted hand-in-hand with studies to understand the development and proliferation of resistance in the multidrug resistant microbes being targeted in this Subproject. Overarching Goals: Determine what genetic or biological events led to the breach of containment of vancomycin resistance in VRE and transfer to VRSA, and demonstrate the activity of new compounds against them, by discovering and examining: -a known genetic event (insertional inactivation of a plasmid borne postsegregational killing TA module), - unknown traits within the genomes of the 10 well documented VRSA strains, and the putative VRE donors coisolated with them, - genetic and metabolic compatibilities, that may have predisposed them to coexist in mixed infection or participate in vancomycin resistance transfer, and - the efficacy of compounds developed in this PPG against these highly multidrug resistant, hospital adapted strains By understanding the basis for transfer as well as the nature of these increasingly resistant strains, we will be better positioned to assess the threat of continued erosion of antibiotic sensitivity in leading causes of hospital and community infection in the US, and will be alert to the types of conditions that promote this transfer.