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性很强的人类寄生虫，既是共生菌又是重要的病原体，它导致多种传染病，从轻微的皮肤脓肿到需要住院治疗的严重感染和中毒。对几乎所有 β-内酰胺具有耐药性的金黄色葡萄球菌菌株，即所谓的耐甲氧西林金黄色葡萄球菌 (MRSA)，是导致医疗保健相关疾病的主要原因自 20 世纪 90 年代以来，社区相关感染的流行增加了寻找成功治疗的替代抗微生物剂的紧迫性。本申请涉及金黄色葡萄球菌菌株中保守的并编码三组分的 vra 操纵子。信号转导系统，可感知并响应临床上重要的抗菌药物引起的细胞壁应激。MRSA 菌株中 vra 操纵子的实验中断显着降低了最小抑制作用。因此，我们希望探索小分子对 vra 操纵子的抑制可能增强 β-内酰胺抗生素（如苯唑西林）杀死 MRSA 菌株和治疗由 MRSA 引起的感染的能力。由于 vra 操纵子表达是由许多化学类别的细胞壁试剂诱导的，因此我们确定的苯唑西林增强剂也可能增强多种其他药物的活性。干扰细胞壁合成的抗菌药物，如万古霉素、阳离子肽和达托霉素。