Targeting Staphylococcus aureus Virulence

针对金黄色葡萄球菌毒力

• 批准号: 8245570
• 负责人: Hattie D. Gresham
• 金额: --
• 依托单位: ALBUQUERQUE VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8245570
• 关键词: Acids; Adult; Affect; Animal Model; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Apolipoproteins B; Attenuated; Binding; Biological Assay; Catheters; Cells; Community Hospitals; Complex; Cyclodextrins; Data; Dose; Drug Delivery Systems; FOLH1 gene; Goals; Gram-Negative Bacterial Infections; Growth; Health Care Costs; Hemolysin; Hospital Costs; Host Defense; Immune; Immunocompetent; In Vitro; Infection; Infectious Skin Diseases; Life; Lipase; Lipids; Long-Term Care; Lytic; Microbial Biofilms; Modeling; Morbidity - disease rate; Mus; Nose; Operon; Oxidants; Oxidases; Phagocytes; Pharmaceutical Preparations; Proteomics; Public Health; Resistance; Resistance development; Route; Screening Result; Screening procedure; Signal Transduction; Soldier; Staphylococcus aureus; Testing; Therapeutic; Time; Transcriptional Regulation; Translating; Treatment Efficacy; Veterans; Virulence; Virulence Factors; Work; antimicrobial peptide; combat; drug development; in vitro Assay; in vivo; inhibitor/antagonist; interest; killings; methicillin resistant Staphylococcus aureus; mortality; mutant; novel strategies; novel therapeutics; pathogen; pathogenic bacteria; public health relevance; quorum sensing; resistant strain; small molecule; staphyloxanthin; success; synergism

DESCRIPTION (provided by applicant): Methicillin resistant Staphylococcus aureus (MRSA) has emerged as a major public health threat and the expansion worldwide of a single clone (USA300) associated with life threatening infections even in immunocompetent adults has re-focused interest in developing novel therapeutics to treat this infection. One strategy emerging to treat antibiotic resistant infections is to develop drugs that target virulence but not bacterial growth. This approach is postulated to limit the development of resistance while enhancing host defense by permitting immune effectors to kill and clear the pathogenic bacteria rendered avirulent by the drug. Whereas this strategy has had success in a few animal models of primarily gram-negative bacterial infection, it has not been pursued for treatment of MRSA infection. The virulence factors identified to date as essential for invasive MRSA infection are globally regulated in part by a quorum sensing operon, agr Importantly, our recent work identifying apolipoprotein B as an innate barrier that antagonizes agr signaling demonstrates that host defense against invasive infection can be accomplished by blocking agr signaling. Therefore, we propose to use small molecule inhibitors (SMIs) identified by screening >50,000 compounds for antagonism of agr to treat experimental MRSA infections. A significant barrier in translating in vitro screening results to successful treatment of infection in vivo is ascertaining an appropriate vehicle for solubilizing these largely hydrophobic compounds while maintaining pharmacologic utility (9). In preliminary data we show that two SMIs complexed with cyclodextrin as a vehicle demonstrate excellent in vivo therapeutic efficacy against quorum sensing dependent MRSA infection. The goal of this Merit Review is to test the hypothesis that small molecule inhibitors complexed with cyclodextrin that attenuate virulence in vitro will enhance host defense against MRSA infection in vivo. To test this hypothesis, we will pursue the following specific aims: 1) To determine the virulence mechanisms affected by small molecule inhibitors complexed with cyclodextrin in both agr+ and Dagr USA300 and USA400 S. aureus strains; 2) To determine in multiple models of agr+ and Dagr S. aureus infection the efficacy and potency of small molecule inhibitors complexed with cyclodextrin, including synergism with existing antibiotics; and 3) To determine the efficacy of innate immune effectors in killing and clearance of agr+ and Dagr USA300 and USA400 S. aureus strains treated with small molecule inhibitors complexed with cyclodextrin. PUBLIC HEALTH RELEVANCE: S. aureus infections are a significant cause of morbidity and mortality in hospitalized veterans, veterans in long-term care facilities, and in soldiers wounded in combat. Antibiotic resistance is increasing in this pathogen and the emergence of hypervirulent antibiotic-resistant strains in both community- and hospital- settings is raising alarm over the continued efficacy of antibiotics for the treatment of this infection. Moreover, treatment of severe antibiotic resistant S. aureus infections is associated with significantly increased hospital costs. Therefore, novel approaches to drug development could both limit serious infection in veterans and assist the VA in limiting health care costs of infected veterans.

描述（由申请人提供）： 耐甲氧西林金黄色葡萄球菌（MRSA）已成为一种主要的公共卫生威胁，并且在全球范围内，一个克隆（USA300）的扩张，即使在免疫能力的成年人中，与生命威胁性感染有关的单一克隆（USA300）也重新集中了对这种新型治疗剂治疗这种感染的兴趣。一种治疗抗生素耐药性感染的策略是开发靶向毒力而非细菌生长的药物。假定这种方法是为了限制抗药性的发展，同时通过允许免疫效应子杀死和清除该药物的无毒细菌。尽管该策略在一些主要是革兰氏阴性细菌感染的动物模型中取得了成功，但尚未追求MRSA感染的治疗。迄今为止确定为侵入性MRSA感染至关重要的毒力因子在全球范围内由群体传感操纵子（AGR）的部分调节，AGR重要的是，我们最近确定载脂蛋白B作为拮抗AGR信号的先天屏障，该障碍物表明，可以通过阻止AGR信号来实现宿主防御的宿主防御。因此，我们建议使用通过筛选> 50,000种为AGR拮抗作用的化合物鉴定出的小分子抑制剂（SMI）来治疗实验性MRSA感染。将体外筛查结果转化为成功治疗体内感染的一个显着障碍是确定在维持药理学实用程序的同时，确定了溶解这些很大程度上疏水化合物的合适载体（9）。在初步数据中，我们表明，两种与环糊精作为载体复合的SMI在体内具有出色的体内治疗功效，以抗群体感应依赖于MRSA的MRSA感染。这项优点综述的目的是检验以下假设：与环糊精在体外减弱毒力的小分子抑制剂将增强对体内MRSA感染的宿主防御。为了检验这一假设，我们将追求以下特定目的：1）确定由小分子抑制剂与环糊精在AGR+和DAGR USA300和USA400 S. AUREUS菌株中与环糊精相辅相成的毒力机制； 2）确定在多种模型的Agr+和Dagr S.金黄色的感染中，与环糊精复合的小分子抑制剂的功效和效力，包括与现有抗生素的协同作用； 3）为了确定先天免疫效应子在杀死和清除Agr+和Dagr USA300和USA400 S.金黄色葡萄球菌菌株中用小分子抑制剂处理的金黄色葡萄球菌菌株的功效。 公共卫生相关性： 金黄色葡萄球菌感染是住院医师，长期护理设施中的退伍军人以及战斗中受伤的士兵的发病率和死亡率的重要原因。在这种病原体中，抗生素耐药性正在增加，在社区和医院环境中，抗生素抗生素抗性菌株的出现正在引起抗生素治疗这种感染的持续有效性的警报。此外，严重抗生素链球菌感染的治疗与医院成本显着增加有关。因此，新颖的药物开发方法既可以限制退伍军人的严重感染，又可以帮助VA限制受感染退伍军人的医疗保健费用。