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: 9240572
• 负责人: Robert S. Daum
• 金额: $ 49.42万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-15 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9240572
• 关键词: Animal Model; Antibiotic Resistance; Antibiotics; Bacterial Drug Resistance; Binding; Binding Proteins; Biological Assay; Biosensor; Cations; Cell Wall; Cells; Chemicals; Chemosensitization; Clinical; Communicable Diseases; Communities; DNA Binding; Daptomycin; Development; Dimerization; Electrostatics; Epidemic; Gene Cluster; Genetic; Genetic Transcription; Half-Life; Healthcare; Hospitalization; Human; In Vitro; Infection; Infectious Skin Diseases; Interruption; Lead; Life; Ligands; Luc Gene; Lung; Metabolic; Methicillin; Methicillin Resistance; Minor; Modeling; Monobactams; Mus; Mutagenesis; Operon; Oxacillin; Parasites; Pathway interactions; Peptides; Phase; Phenotype; Phosphorylation; 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; Symbiosis; Techniques; Testing; Toxic effect; Validation; Vancomycin; antimicrobial; antimicrobial drug; base; beta-Lactams; cell growth; cytotoxicity; design; dimer; efficacy testing; improved; in vitro testing; in vivo; inhibitor/antagonist; killings; novel therapeutics; pathogen; pre-clinical; promoter; public health relevance; resistant strain; scaffold; screening; skin abscess; small molecule; synergism; virtual

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.

描述（由申请人提供）：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，也是重要的病原体。它是各种各样的传染病的罪魁祸首，从轻微的皮肤脓肿到严重的感染和需要住院治疗的毒素。金黄色葡萄球菌菌株对几乎所有ß-内酰胺具有耐药性，即所谓的耐甲氧西林金黄色葡萄球菌（MRSA），是医疗保健相关感染的主要原因，自20世纪90年代以来，也是社区相关感染的主要原因。这种耐甲氧西林金黄色葡萄球菌感染的流行增加了确定替代抗菌药物以成功治疗的紧迫性。目前的应用涉及在金黄色葡萄球菌菌株中保守的vra操纵子，该操纵子编码一个三组分信号转导系统，该系统感知并响应临床重要抗菌素引起的细胞壁应激。实验中断MRSA菌株的vra操纵子可显著降低oxacillin（甲氧西林同系物）在MRSA菌株中的最低抑制浓度。因此，我们希望探索小分子抑制vra操纵子可能增强ß-内酰胺类抗生素（如oxacillin）杀死MRSA菌株并治疗由其引起的感染的能力。由于vra操纵子的表达可由多种化学类别的细胞壁药物诱导，因此我们鉴定的oxacillin增强剂也可能增强多种其他干扰细胞壁合成的抗菌剂的活性，如万古霉素、阳离子肽和达托霉素。