CYTOMETRY-AIDED DEVELOPMENT OF ANTIMICROBIAL AGENTS

细胞计数辅助抗菌剂的开发

• 批准号: 6344008
• 负责人: HOWARD M. SHAPIRO
• 金额: $ 8.15万
• 依托单位: HOWARD M. SHAPIRO, MD, P.C.
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-01 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6344008
• 关键词: acid base balance; antiinfective agents; drug design /synthesis /production; drug resistance; flow cytometry; fluorescent dye /probe; membrane permeability; membrane potentials; method development; microorganism metabolism; tetracyclines

DESCRIPTION (provided by applicant): There has recently been an alarming increase in infections due to bacteria resistant to all available antibiotics. Tetracycline resistance is typically mediated by efflux pumps; tetracycline derivatives which inhibit them may be used in combination with existing tetracyclines to treat infections by resistant organisms. Flow cytometric methods will be developed to facilitate measurement of tetracycline uptake and efflux in bacteria, and detection of effects of tetracyclines and daptomycin on membrane potential, pH, and permeability. Another method of potentiating existing antibiotics is suggested by the finding that bacteria treated with sublethal doses of some antibiotics become transiently permeable to dyes that normally do not penetrate the membranes of either bacterial or mammalian cells. The chemical modifications used to make dyes impermeant can be applied to various toxic agents; these modified agents should be nontoxic to host cells, but kill transiently permeabilized bacteria. This hypothesis, which may provide a novel and general therapeutic approach to bacterial infections, will be tested using fluorescent nucleic acid binding compounds with known permeant and impermeant characters; antibiotic-sensitive and -resistant Staphylococcus and Enterococcus species and Escherichia coli will be examined. PROPOSED COMMERCIAL APPLICATION: There is a substantial market in drug companies and research institutions for assays and related instrumentation which facilitate rapid development of new antimicrobial agents. Moreover, drugs or combinations which improved treatment of infections due to even a few antibiotic-resistant bacterial species would capture a significant share of a huge market for antibacterial agents.

描述（由申请人提供）：最近出现了令人震惊的情况 由于细菌对所有可用抗生素具有抗药性，导致感染增加。 四环素耐药性通常是由外排泵介导的；四环素 抑制它们的衍生物可以与现有的组合使用 四环素用于治疗耐药微生物的感染。流式细胞仪 将开发方法以方便测量四环素的吸收和 细菌的外排，并检测四环素和达托霉素对细菌的影响 膜电位、pH 值和渗透性。另一种增强方法 现有抗生素的发现表明，经过处理的细菌 一些亚致死剂量的抗生素会短暂地被染料渗透， 通常不穿透细菌或哺乳动物细胞的膜。 用于使染料不渗透的化学修饰可应用于 各种有毒物质；这些修饰剂应该对宿主细胞无毒， 但会暂时杀死透化细菌。这个假设可能提供 一种针对细菌感染的新颖且通用的治疗方法将是 使用具有已知渗透性和渗透性的荧光核酸结合化合物进行测试 不渗透的字符；对抗生素敏感和耐药的葡萄球菌和 将检查肠球菌和大肠杆菌。 拟议的商业应用： 制药公司和研究机构在检测和分析方面有很大的市场。 相关仪器可促进新型抗菌药物的快速开发。 此外，改善感染治疗的药物或组合，甚至是由于 一些对抗生素具有抗药性的细菌物种将占据巨大的份额 抗菌剂市场。