Antibiotic Potentiation by Targeting of a Signal Transduction System

项目摘要/摘要 金黄色葡萄球菌是一种适应良好的人类寄生虫，既是共生的又是重要的病原体。 它导致多种传染病，从轻微的皮肤脓肿到严重的 需要住院治疗的感染和中毒。金黄色葡萄球菌对几乎所有的SS-内酰胺类耐药，即所谓的 耐甲氧西林金黄色葡萄球菌(MRSA)是医疗保健相关的主要原因，自20世纪90年代以来， 社区相关感染。耐甲氧西林金黄色葡萄球菌感染的流行增强了确定 成功治疗的替代抗菌剂。本申请涉及VRA操纵子 在S金黄色葡萄球菌菌株中保守，并编码一个三组分的信号转导系统 并对临床上重要的抗菌药引起的细胞壁压力做出反应。实验性地中断了 MRSA菌株中的VRA操纵子显著降低苯唑西林的最低抑菌浓度 耐甲氧西林金黄色葡萄球菌中的甲氧西林同系物。因此，我们希望探索VRA操纵子被小分子抑制的想法 分子可能会增强SS-内酰胺类抗生素，如苯唑西林，杀死MRSA菌株和 治疗由它们引起的感染。由于VRA操纵子表达是由许多细胞壁剂诱导的 化学类，我们确定的苯唑西林增效剂也可以增强多种其他 干扰细胞壁合成的抗菌剂，如万古霉素、阳离子多肽和达托霉素。

PROJECT SUMMARY/ABSTRACT Staphylococcus aureus is a well-adapted human parasite that is both a commensal and an important pathogen. It is responsible for a wide variety of infectious diseases that range from minor skin abscesses to severe infections and toxinoses requiring hospitalization. S. aureus strains resistant to nearly all ss-lactams, so-called methicillin-resistant S. aureus (MRSA), are a leading cause of healthcare associated and, since the 1990s, community-associated infections. This epidemic of MRSA infections has enhanced the urgency to identify alternative antimicrobial agents for successful treatment. The present application concerns the vra operon that is conserved among S aureus strains and encodes a three-component signal transduction system that senses and responds to cell-wall stress elicited by clinically important antimicrobials. Experimental interruption of the vra operon in a MRSA strain dramatically decreases the minimal inhibitory concentration of oxacillin, a methicillin congener, in MRSA strains. Thus, we wish to explore the idea that vra operon inhibition by small molecules may enhance the ability of ss-lactam antibiotics, such as oxacillin, to kill MRSA strains and treat infections caused by them. Since vra operon expression is induced by cell-wall agents from many chemical classes, the oxacillin potentiators we identify may also enhance activity of a wide variety of other antimicrobials that interfere with cell-wall synthesis such as vancomycin, cationic peptides and daptomycin.