Antibiotic Potentiation by Targeting of a Signal Transduction System

通过靶向信号转导系统增强抗生素

• 批准号: 8703981
• 负责人: SUSAN BOYLE-VAVRA
• 金额: $ 21.28万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8703981
• 关键词: Animal Model; Antibiotic Resistance; Antibiotics; Bacterial Drug Resistance; Binding; Biological Assay; Biosensor; Cell Wall; Cells; Chemicals; Chemosensitization; Clinical; Communicable Diseases; Communities; DNA Binding; Daptomycin; Development; Dimerization; Electrostatics; Epidemic; Gene Cluster; Genetic; Half-Life; Healthcare; Hospitalization; Human; In Vitro; Infection; Infectious Skin Diseases; Interruption; Lactams; Lead; Life; Ligands; Luc Gene; Lung; Metabolic; Methicillin; Minor; Modeling; Monobactams; Mus; Mutagenesis; Operon; Oxacillin; Parasites; Pathway interactions; Peptides; Phase; Phenotype; Phosphorylation; Protein Binding; Proteins; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Rodent Model; Serum Proteins; Shapes; Signal Transduction; Skin; Staphylococcus aureus; Stress; Structure; Structure-Activity Relationship; Surface Plasmon Resonance; Techniques; Testing; Toxic effect; Validation; Vancomycin; Work; antimicrobial; antimicrobial drug; base; cell growth; cytotoxicity; design; efficacy testing; improved; in vitro testing; in vivo; inhibitor/antagonist; killings; methicillin resistant Staphylococcus aureus; novel therapeutics; pathogen; pre-clinical; promoter; public health relevance; resistant strain; scaffold; screening; skin abscess; small molecule; virtual

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.

项目总结/摘要 金黄色葡萄球菌（Staphylococcus aureus）是一种适应性很强的人类寄生虫，既是寄生虫又是重要的病原体。 它是负责各种各样的传染病，范围从轻微的皮肤炎症到严重的 需要住院治疗的感染和中毒。S.金黄色葡萄球菌菌株对几乎所有的β-内酰胺类抗生素都有耐药性， 耐甲氧西林表皮葡萄金黄色葡萄球菌（MRSA）是与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。MRSA感染的流行增强了识别 替代抗菌药物以成功治疗。本申请涉及弗拉操纵子，其 在金黄色葡萄球菌菌株中是保守的，编码一个三组分信号转导系统， 并对由临床上重要的抗菌剂引起的细胞壁应激作出反应。实验性中断 MRSA菌株中的弗拉操纵子显著降低苯唑西林的最小抑菌浓度， 甲氧西林同系物，在MRSA菌株中。因此，我们希望探索这样一种想法，即小分子抑制剂对弗拉操纵子的抑制作用可能是一种新的机制。 分子可以增强β-内酰胺抗生素如苯唑西林杀死MRSA菌株的能力， 治疗由它们引起的感染。由于弗拉操纵子的表达是由来自多种细胞的细胞壁因子诱导的， 化学类别，我们确定的苯唑西林增效剂也可以增强多种其他药物的活性。 干扰细胞壁合成的抗菌剂，如万古霉素、阳离子肽和达托霉素。