Bactericidal agents for slow-growing bacteria

针对生长缓慢的细菌的杀菌剂

• 批准号: 6643040
• 负责人: Penelope N. Markham
• 金额: $ 4.8万
• 依托单位: PROTEZ PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2003-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6643040
• 关键词: Staphylococcus aureus; antibacterial agents; biofilm; cell growth regulation; cell line; chemical registry /resource; drug design /synthesis /production; drug screening /evaluation; human tissue; pyridine; thioether

DESCRIPTION (provided by applicant): In many chronic infections, including all biofilm related infections, the slow growth of bacteria is believed to account not only for resistance to antibiotics, but also for the high incidence of persistence and relapse. Considering that all currently prescribed antibiotics are significantly more effective against rapidly growing pathogens, the development of antibiotics highly effective against bacteria in the slow mode of growth is of utmost importance. By screening a chemical library for compounds bactericidal for slow-growing S. aureus, we have succeeded in identifying a very promising class of compounds, pyridinium thiol ethers (PTEs). Preliminary data indicate that PTEs are not only effective against fluid-phase S. aureus, but also against biofilms as well as against other bacteria in a slow mode of growth. In the proposed Phase I project, we will synthesize and screen a library of PTEs in order to identify compounds that will be bactericidal against slow and logarithmically growing S. aureus. Feasibility of the medical use of the most active derivatives will be analyzed. Finally, the basic principles underlying the molecular mechanism of action of PTE compounds will be investigated. The Phase I project will provide the basis for the Phase II project, which will involve chemical improvement of the lead compounds, investigation of their activity in various biofilm models, and in vivo toxicology studies. PTE compounds could provide a unique opportunity for eradication of infections associated with slow bacterial growth.

描述（由申请人提供）：在许多慢性感染中，包括所有与生物膜相关的感染，细菌生长缓慢被认为不仅是对抗生素产生耐药性的原因，而且也是持续性和复发率高的原因。考虑到目前所有处方抗生素对快速生长的病原体都显着更有效，因此开发对缓慢生长模式的细菌高效的抗生素至关重要。通过筛选对生长缓慢的金黄色葡萄球菌具有杀菌作用的化合物的化学库，我们成功地鉴定出了一类非常有前途的化合物：吡啶硫醇醚 (PTE)。初步数据表明，PTE 不仅能有效对抗液相金黄色葡萄球菌，还能有效对抗生物膜以及其他缓慢生长的细菌。在拟议的第一阶段项目中，我们将合成和筛选 PTE 库，以确定对缓慢且对数生长的金黄色葡萄球菌具有杀菌作用的化合物。将分析最活跃的衍生物的医疗用途的可行性。最后，将研究 PTE 化合物作用分子机制的基本原理。第一阶段项目将为第二阶段项目提供基础，第二阶段项目将涉及先导化合物的化学改进、研究其在各种生物膜模型中的活性以及体内毒理学研究。 PTE 化合物可以为根除与细菌生长缓慢相关的感染提供独特的机会。