Development of Novel Inhibitors of Clostridium difficile.

艰难梭菌新型抑制剂的开发。

• 批准号: 8277010
• 负责人: Jane Ryan
• 金额: $ 52.89万
• 依托单位: BIOTA SCIENTIFIC MANAGEMENT
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-15 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8277010
• 关键词: ADME Study; Anti-Bacterial Agents; Antibiotics; Benchmarking; Biological Assay; Biota; Cell division; Cells; Chemicals; Clinical; Clostridium difficile; Communities; Country; Data; Development; Dose; Drug Formulations; Drug Kinetics; Ensure; Goals; Guidelines; Healthcare; Hospital Costs; Hospitals; In Vitro; Infection; Innovative Therapy; Intestines; Intravenous; Investigation; Lead; Oral; Oral Administration; Outcome; Patients; Permeability; Pharmacodynamics; Phase; Population; Property; Rattus; Recurrence; Reproduction spores; Research; Resistance; Resistance profile; Route; Selection Criteria; Temperature; Testing; Toxicology; base; candidate selection; clinical toxicology; effective therapy; high risk; improved; in vitro testing; in vivo; inhibitor/antagonist; innovation; lead series; manufacturing process development; meetings; novel; plasma protein Z; pre-clinical; prevent; programs; success; transmission process

DESCRIPTION (provided by applicant): Development of lead compounds of a novel class of FtsZ inhibitor compounds to provide an improved treatment for Clostridium difficile infection (CDI) C. difficile is one of the most important causes of health care-associated infections; US annual excess hospital costs have been estimated at $3.2 billion per annum. Current antibacterial therapy disrupts intestinal flora and leaves patients susceptible to recurrences. Whilst a proportion of recurrences may be due to persistent intestinal spores, no current therapy targets sporulation. The transmission and persistence of spores also leads to the inability to prevent CDI in high-risk settings. The hypothesis is that the targeted treatment of both cell division and sporulation by an intestinal-flora sparing agent will provide an innovative and effective therapy, and it is anticipated that this will deliver the added benefits of a reduction in recurrence and transmissibility. Biota's novel FtsZ inhibitor compounds possess potency against C. difficile, including the hypervirulent BI/NAP1/027 strain which now appears to be emerging in wider populations. The compounds are anticipated to target both vegetative clostridial cells as well as clostridial sporulation and are also anticipated to be bacteriocidal, narrow spectrum, and importantly, intestinal flora sparing. In addition, this new class of antibiotic acts by a different mechanism of action to others in development, offering a distinct resistance/cross- resistance profile. Optimization and early development of the lead compounds as outlined in this proposal will be undertaken to enhance the properties necessary to effectively treat CDI. Identification of preclinical candidates will focus primarily on an oral formulation that offers optimal antibacterial activity localized to the gut. Success in this program would offer a development candidate with excellent prospects as an innovative, economical and effective CDI therapy suitable for registration in the U.S. and other countries: a novel, orally delivered, intestinal-flora sparing FtsZ-inhibitor. The predicted targeting of C. difficile cell division and sporulation by this novel antibiotic is anticipated to provide the added benefits of a reduction in recurrence and transmissibility.

描述（由申请人提供）：新型FTSZ抑制剂化合物的铅化合物的开发，以改善艰难梭菌感染（CDI）艰难梭菌的治疗方法是医疗保健相关感染的最重要原因之一；美国年度超额医院费用估计为每年32亿美元。当前的抗菌治疗会破坏肠道菌群，使患者容易复发。虽然一定比例的复发可能是由于持续的肠孢子引起的，但没有当前的治疗靶向孢子。孢子的传播和持久性也导致无法在高危设置中防止CDI。假设是，肠道菌株对细胞分裂和孢子形成的靶向治疗将提供一种创新有效的治疗，预计这将带来降低复发性和可传播性的额外好处。 Biota的新型FTSZ抑制剂化合物具有针对艰难梭菌的效力，其中包括高毒性的BI/NAP1/027菌株，该菌株现在在更广泛的种群中似乎正在出现。预计这些化合物可以靶向营养性梭状芽胞杆菌细胞和梭孢子孢子，并且也预计将是杀菌性，狭窄的光谱，并且重要的是肠菌群的散发。此外，这类新的抗生素通过与开发中的其他人的不同作用机理起作用，提供了独特的抗性/交叉电阻概况。将在本提案中概述的铅化合物的优化和早期开发，以增强有效治疗CDI所需的特性。临床前候选者的识别将主要集中在口服配方上，该配方提供局部局部的最佳抗菌活性。该计划的成功将为一名具有出色前景的发展候选人作为一种创新，经济和有效的CDI疗法，适合在美国和其他国家 /地区注册：一种新颖的，口服的，口服的，肠道五氯酸国际抗体的抑制剂。预计艰难梭菌细胞分裂和这种新型抗生素的孢子形成的预测靶向可提供降低复发性和可传播性的额外好处。