Development of a mechanistically novel synergistic adjuvant to partner with polymyxin antibiotics

开发一种与多粘菌素抗生素配合使用的新型机械协同佐剂

• 批准号: 10481682
• 负责人: Terry Roemer
• 金额: $ 30万
• 依托单位: PROKARYOTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10481682
• 关键词: 3-Dimensional; Acinetobacter; Acinetobacter Infections; Acinetobacter baumannii; Address; Adjuvant; Adverse effects; Affect; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Bacteremia; Binding Proteins; Biological Assay; Bioreactors; Blood; Carbapenems; Ceftriaxone; Cell Wall; Cells; Centers for Disease Control and Prevention (U.S.); Chemicals; Chemosensitization; Clinical; Colistin; Collaborations; Data Set; Development; Dose; Dose Fractionation; Drug Efflux; Drug Kinetics; Exhibits; Family; Fermentation; Frequencies; Goals; Gonorrhea; In Vitro; Infection; Knowledge; Lactams; Lead; Letters; Lung; Lung infections; Measures; Medical; Membrane; Methodology; Microbiology; Modeling; Monitor; Multi-Drug Resistance; Multidrug-resistant Acinetobacter; Mus; Natural Products; Nosocomial pneumonia; Outcome; Penicillin-Binding Proteins; Peptidoglycan; Peptidyltransferase; Peritonitis; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Phenotype; Plasma Proteins; Polymers; Polymyxin B; Polymyxin B resistance; Polymyxin Resistance; Polymyxins; Process; Production; Property; Protocols documentation; Reducing Agents; Research; Resistance; Resort; Septicemia; Series; Structure; Structure-Activity Relationship; Tail; Therapeutic Index; Thigh structure; Toxicology; Treatment-related toxicity; Urinary tract infection; Work; analog; bactericide; base; bioprocess; carbapenem resistance; clinically relevant; colistin resistance; cytotoxicity; design; efficacy testing; flasks; improved; in vivo; in vivo evaluation; inhibitor; large scale production; lead optimization; lead series; lipophilicity; moenomycin A; mortality; mouse model; nephrotoxicity; novel; pathogen; pre-clinical; resistance mechanism; scale up; standard of care; structural biology; synergism; wound

Acinetobacter baumannii (Ab) and related spp. cause severe nosocomial pneumonia, wound, blood, and urinary tract infections, with mortality rates ranging from 25-75%. The emergence of multidrug-resistant (MDR) Ab isolates has made it difficult to treat with most standard-of-care antibiotics. Carbapenems have served as the preferred therapy to treat Ab infections, however, over 50% of infections are now carbapenem-resistant Ab (CRAB). Consequently, the WHO and CDC have classified CRAB as a PRIORITY-1 CRITICAL and URGENT threat pathogen. Polymyxin B (PMB) and colistin have become the antibiotics of last resort to treat CRAB despite their low therapeutic index due to potential nephrotoxicity. To address this unmet medical need, we aim to develop an effective combination agent comprising a polymyxin potentiator and an efficacious, mechanistically novel antibiotic, medinamycin (MedM). MedM is unaffected by clinically relevant modes of antibiotic resistance, exhibits low FOR and provides robust synergistic bactericidal activity against Ab, including colistin-resistant, MDR, and CRAB isolates, and is predicted to be a safe and effective antibiotic to permit lower effective doses of PMB, thereby reducing adverse effects. Aim 1 (Phase 1) Validate the feasibility of developing semisynthetic MedM analogs effective in combination with PMB and/or SPR741 against polymyxinR Ab. Improve MedM bioprocess to deliver >1 g for Aim 1 studies. Demonstrate chemical tractability. Develop the structure activity relationship (SAR) of new analogs using MOA, FOR, microbiological activity, and cytotoxicity assays. Demonstrate in vivo efficacy of a MedM analog + PMB against a PMBR Ab isolate in murine bacteremia infection model. Aim 2 (Phase 2) Complete bioprocess optimization and conduct a semisynthetic lead optimization with the goal of identifying MedM analogs with improved potency and/or drug like properties. Increase reliable production levels of MedM to >250 mg/L using 20L bioreactors, eventually producing 30 g of MedM. Using this material, prepare up to 150 semisynthetic analogs in an iterative fashion according to emerging SAR. Measure Ab MIC for all compounds, and for select compounds evaluate synergistic inhibitory concentration with potential polymyxin partners, in vitro tox and ADME, FOR, kill curves, PK and MIC90 to select polymyxin partner and analogs to advance to in vivo testing in Aim 3. Aim 3 (Phase 2) In vivo characterization of MedM analogs in combination with selected potentiator in relevant mouse models of Ab infection to identify lead series of combination product. Test efficacy of superior MedM analogs + polymyxin potentiator against a PMBR Ab clinical isolate in a mouse peritonitis infection model, followed by a deep thigh and neutropenic mouse lung infection model. In each study, demonstrate that a MedM analog provides statistically significant efficacy (P < 0.05) if combined with polymyxin at a sub-efficacious dose to identify lead MedM series for combination product. Dose fractionation studies will also be performed.

鲍曼不动杆菌 (Ab) 和相关菌种。引起严重的院内肺炎、伤口、血液和尿液 道感染，死亡率为 25-75%。多重耐药（MDR）抗体的出现 分离株使得大多数标准护理抗生素难以治疗。碳青霉烯类药物已作为 治疗抗体感染的首选疗法，然而，现在超过 50% 的感染是碳青霉烯类耐药抗体 （螃蟹）。因此，世界卫生组织和疾病预防控制中心已将 CRAB 列为 PRIORITY-1 严重且紧急 威胁病原体。多粘菌素 B (PMB) 和粘菌素已成为治疗 CRAB 的最后手段的抗生素，尽管 由于潜在的肾毒性，它们的治疗指数较低。为了解决这一未满足的医疗需求，我们的目标是 开发一种有效的组合药物，包含多粘菌素增效剂和有效的、机械的 新型抗生素，麦地那霉素（MedM）。 MedM 不受临床相关抗生素耐药性模式的影响， 表现出低 FOR 并针对 Ab 提供强大的协同杀菌活性，包括粘菌素抗性、 MDR 和 CRAB 分离株，预计将成为一种安全有效的抗生素，可降低有效剂量 PMB，从而减少不良影响。 目标 1（第一阶段）验证开发有效的半合成 MedM 类似物的可行性 与 PMB 和/或 SPR741 联合抗多粘菌素 R 抗体。改进 MedM 生物工艺，以提供 >1 g 目标1研究。展示化学易处理性。开发新的结构活性关系（SAR） 使用 MOA、FOR、微生物活性和细胞毒性测定来分析类似物。证明体内功效 MedM 类似物 + PMB 对抗鼠菌血症感染模型中的 PMBR Ab 分离株。 目标 2（第 2 阶段）完成生物工艺优化并进行半合成先导化合物优化 识别具有改进效力和/或类似药物特性的 MedM 类似物的目标。增加可靠性 使用 20L 生物反应器将 MedM 的产量水平提高到 >250 mg/L，最终生产 30 g MedM。使用这个 材料，根据新兴 SAR 以迭代方式制备多达 150 种半合成类似物。措施 所有化合物以及选定化合物的 Ab MIC 评估潜在的协同抑制浓度 多粘菌素伴侣、体外毒性和 ADME、FOR、杀伤曲线、PK 和 MIC90，用于选择多粘菌素伴侣和 类似物推进到目标 3 中的体内测试。 目标 3（第 2 阶段）MedM 类似物与所选增强剂组合的体内表征 Ab感染的相关小鼠模型，以确定组合产品的先导系列。测试功效 卓越的 MedM 类似物 + 多粘菌素增效剂针对小鼠腹膜炎感染中的 PMBR Ab 临床分离株 模型，然后是大腿深部和中性粒细胞减少的小鼠肺部感染模型。在每项研究中，证明 如果与亚有效的多粘菌素联合使用，MedM 类似物可提供统计学上显着的疗效 (P < 0.05) 确定组合产品的主要 MedM 系列的剂量。还将进行剂量分割研究。