Antibiotic Potentiation by Targeting of a Signal Transduction System

描述（由申请方提供）：金黄色葡萄球菌是一种适应性良好的人类寄生虫，既是寄生虫，也是重要的病原体。它是造成各种各样的传染病的原因，从轻微的皮肤病到需要住院治疗的严重感染和中毒。S.金黄色葡萄球菌菌株对几乎所有的β-内酰胺类抗生素都具有耐药性，即所谓的耐甲氧西林金黄色葡萄球菌。金黄色葡萄球菌（MRSA）是医疗保健相关感染的主要原因，并且自20世纪90年代以来，是社区相关感染的主要原因。MRSA感染的流行增加了确定成功治疗的替代抗菌药物的紧迫性。本申请涉及在S.金黄色葡萄球菌菌株并编码三组分信号转导系统，该系统感知并响应由临床上重要的抗微生物剂引起的细胞壁应激。在MRSA菌株中实验性中断弗拉操纵子可显著降低苯唑西林（甲氧西林同源物）在MRSA菌株中的最小抑菌浓度。因此，我们希望探索小分子对弗拉操纵子的抑制可以增强β-内酰胺抗生素如苯唑西林杀死MRSA菌株和治疗由它们引起的感染的能力.由于弗拉操纵子表达是由许多化学类别的细胞壁试剂诱导的，我们鉴定的苯唑西林增效剂也可能增强多种干扰细胞壁合成的其他抗菌剂如万古霉素、阳离子肽和达托霉素的活性。

DESCRIPTION (provided by applicant): 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 methicilln-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.