SBIR Phase I: Combating Multi-Drug Resistant Gram-negative Healthcare-Associated Infections

SBIR 第一阶段：对抗多重耐药革兰氏阴性医疗相关感染

• 批准号: 2310453
• 负责人: Christopher Morl
• 金额: $ 27.49万
• 依托单位: BACTRIA PHARMACEUTICALS LLC
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2024
• 资助国家: 美国
• 起止时间: 2024-01-15 至 2024-12-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2310453&HistoricalAwards=false
• 关键词: SBIR; Phase; Combating; Multi; Drug

The broader impact of this Small Business Innovation Research (SBIR) Phase I project is to develop therapeutic drugs that restore antibiotic sensitivity in bacteria that cause severe infections in patients that are hospitalized or receiving healthcare for another condition. Antibiotics are paramount to modern medicine. In addition to treating infections and controlling their spread, these drugs enable safe surgeris, facilitate childbirth, and provide treatments for diseases such as cancer. However, as microbes evolve and develop resistance, these life-saving drugs are losing effectiveness. Eleven potent and specific small molecules have been identified that restore antibiotic sensitivity in these bacteria. Bloodstream infections and ventilator-associated pneumonia caused by Gram-negative bacteria are two severe healthcare associated infections that despite current treatments cause significant excess mortality (150 deaths/1,000 patients), longer hospital stays, and incremental costs estimated at nearly $50,000 per patient. Developing therapeutics that restore the sensitivity of Multi-Drug Resistant (MDR) Gram-negative pathogens to commonly used, well tolerated antibiotics addresses a major unmet medical need and would be transformative for patients and physicians.This project involves developing small molecules to restore the sensitivity of Multi-Drug Resistant (MDR) Gram-negative bacteria to commonly used, well tolerated antibiotics. The role of bacterial efflux pumps in MDR Gram-negative bacteria is well documented. These pumps are virulence determinants essential for infection, and by exporting antibiotics across the bacterial cell envelope they play a key role in antibiotic resistance. Eleven potent and specific small molecule inhibitors of bacterial efflux pumps (EPIs) have been identified. These EPIs are in early-stage lead optimization and this project involves three foundational assays: cryo-electron microscopy (cryo-EM), membrane permeability, and in vitro antibiotic combination assays, followed by in vitro characterization, safety pharmacology, and liability screening. Cryo-EM provides insight into the mechanism of action and binding of these EPIs to the efflux pump, enabling in-silico docking studies and the design of new analogs. Some prior EPI research failed due to membrane permeabilization, a property that can result in apparent in vitro efficacy. Cryo-EM data together with results from in vitro efficacy and membrane permeability assays allows early deselection of poor-quality compounds, focusing screening studies on the most promising EPIs. This project may provide insights into links between MDR, persister cells, and virulence in Gram-negative pathogens.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

该小企业创新研究 (SBIR) 第一阶段项目的更广泛影响是开发治疗药物，以恢复细菌的抗生素敏感性，这些细菌会导致住院或因其他疾病接受医疗保健的患者发生严重感染。抗生素对于现代医学至关重要。除了治疗感染和控制其传播之外，这些药物还可以实现安全手术、促进分娩以及治疗癌症等疾病。然而，随着微生物的进化和耐药性的产生，这些救命药物正在失去效力。已鉴定出十一种有效且特定的小分子，可以恢复这些细菌的抗生素敏感性。由革兰氏阴性菌引起的血流感染和呼吸机相关性肺炎是两种严重的医疗保健相关感染，尽管目前的治疗方法仍会导致死亡率显着过高（150 人死亡/1,000 名患者）、更长的住院时间以及每位患者估计近 50,000 美元的增量成本。开发能够恢复多重耐药 (MDR) 革兰氏阴性病原体对常用、耐受性良好的抗生素敏感性的疗法，解决了一个未满足的重大医疗需求，并将为患者和医生带来变革。该项目涉及开发小分子来恢复敏感性多重耐药 (MDR) 革兰氏阴性菌对常用的、耐受性良好的抗生素。细菌外排泵在耐多药革兰氏阴性细菌中的作用已有充分记录。这些泵是感染所必需的毒力决定因素，通过将抗生素输出到细菌细胞包膜上，它们在抗生素耐药性中发挥着关键作用。已鉴定出 11 种有效且特异性的细菌外排泵 (EPI) 小分子抑制剂。这些 EPI 处于早期先导物优化阶段，该项目涉及三种基础测定：冷冻电子显微镜 (cryo-EM)、膜渗透性和体外抗生素组合测定，然后是体外表征、安全药理学和责任筛选。冷冻电镜可深入了解这些 EPI 的作用机制以及与外排泵的结合，从而实现计算机对接研究和新类似物的设计。之前的一些 EPI 研究因膜透化而失败，这种特性可导致明显的体外功效。冷冻电镜数据与体外功效和膜渗透性测定的结果相结合，可以尽早剔除劣质化合物，将筛选研究集中在最有前途的 EPI 上。该项目可以深入了解 MDR、持久细胞和革兰氏阴性病原体毒力之间的联系。该奖项反映了 NSF 的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。