POTENTIATORS OF BACTERIOSTATIC ANTIBIOTICS IN GRAM +

克制抑菌抗生素的增效剂

• 批准号: 6140009
• 负责人: Penelope N. Markham
• 金额: $ 18.5万
• 依托单位: PROTEZ PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6140009
• 关键词: Staphylococcus; antibacterial agents; antibiotics; chemical structure function; drug design /synthesis /production; drug screening /evaluation; gram positive bacteria; tissue /cell culture; toxicology

There is an urgent need for bactericidal antimicrobial agents effective against Gram positive infections. Although bacteriostatic antibiotics are useful in treating a large number of infections their activity can be limited in situations where it is imperative to eradicate an infection rather than simply stop bacterial growth. We have succeeded in identifying an extremely promising class of compounds, the lead of which, in combination with bacteriostatic concentrations of either erythromycin, chloramphenicol, clindamycin or tetracycline, is synergistically and rapidly bactericidal to S. aureus. Preliminary data indicate that this compound is also effective in S. pneumoniae. In this Phase I project the range of antibiotics potentiated by the lead compound and its bacterial spectrum of activity will be determined. QSAR analysis will be performed on purchased and chemically synthesized analogues of INF 401 with the view of chemically improving its activity and decreasing in vitro toxicity. Additionally the basic principles underlying the molecular mechanism of action of this intriguing compound will be investigated. The Phase I project will provide the basis for the Phase II project which will involve further chemical improvement of the lead compound and in vivo toxicology and efficacy studies.The developed potentiator, combined with existing bacteriostatic antibiotics, can provide a valuable therapeutic alternative when resistance to bactericidal antibiotics limits therapeutic options. PROPOSED COMMERCIAL APPLICATIONS: The envisioned commercial product is the combination of either a macrolide, lincosamide, tetracycline, chloramphenicol, or other bacteriostatic antibiotic, with a potentiator to give a combination that is bactericidal to a range of Gram positive pathogens. Such a combination would provide a valuable therapeutic alternative, especially when resistance to existing antibiotics limits therapeutic options.

迫切需要有效对抗革兰氏阳性感染的杀菌抗微生物剂。尽管抑菌抗生素可用于治疗大量感染，但在必须根除感染而不是简单地阻止细菌生长的情况下，它们的活性可能会受到限制。我们已经成功地鉴定出一类极其有前途的化合物，其中的先导化合物与抑菌浓度的红霉素、氯霉素、克林霉素或四环素结合，对金黄色葡萄球菌具有协同且快速的杀菌作用。初步数据表明该化合物对肺炎链球菌也有效。在这个第一阶段项目中，将确定先导化合物增强的抗生素范围及其细菌活性谱。将对购买的和化学合成的 INF 401 类似物进行 QSAR 分析，以期通过化学方法提高其活性并降低体外毒性。此外，还将研究这种有趣化合物的分子作用机制的基本原理。一期项目将为二期项目提供基础，二期项目将涉及先导化合物的进一步化学改进以及体内毒理学和功效研究。所开发的增效剂与现有的抑菌抗生素相结合，可以在耐药性时提供有价值的治疗替代方案。杀菌抗生素限制了治疗选择。拟议的商业应用：设想的商业产品是大环内酯、林可酰胺、四环素、氯霉素或其他抑菌抗生素与增效剂的组合，以产生对一系列革兰氏阳性病原体具有杀菌作用的组合。这种组合将提供一种有价值的治疗选择，特别是当对现有抗生素的耐药性限制了治疗选择时。