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.)及相关种。引起严重的院内肺炎、伤口、血和尿液 肠道感染，死亡率从25%到75%不等。多药耐药抗体的出现 分离株使大多数标准护理抗生素难以治疗。碳青霉烯类一直是 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，世界卫生组织和疾控中心将螃蟹列为优先事项-1关键和紧急 威胁病原体。多粘菌素B(PMB)和粘菌素已成为治疗螃蟹的最后手段 由于潜在的肾毒性，其治疗指数较低。为了解决这一未得到满足的医疗需求，我们的目标是 研制一种由多粘菌素增强剂和一种有效的、机械的 新型抗生素--麦迪霉素(Medm)。MedM不受临床相关抗生素耐药性模式的影响， 对抗体，包括对粘菌素耐药的抗体，表现出低的杀菌活性并提供强大的协同杀菌活性， MDR和螃蟹分离株，预计将是一种安全有效的抗生素，允许较低有效剂量的 港口及航运局，从而减少不利影响。 目标1(阶段1)验证开发有效的半合成MedM类似物的可行性 PMB和/或SPR741联合抗多粘菌素R抗体。改进MedM生物工艺以交付1克用于 目的1研究。证明化学物质的易操纵性。发展新的构效关系(SAR) 类似物使用MOA、FOR、微生物活性和细胞毒性测定。在体内展示了一种 MedM类似物+PMB在小鼠菌血症感染模型中对PMBR抗体分离株的作用 目标2(阶段2)完成生物工艺优化，并进行半合成铅优化 目的是确定具有更高效力和/或类药物特性的MedM类似物。提高可靠性 使用20L生物反应器，生产水平为250 mg/L的MedM，最终生产30 g MedM。使用这个 材料，根据正在出现的SAR以迭代的方式准备多达150个半合成类似物。量测 对所有化合物的最低抑菌浓度，对于选定的化合物，用潜在的评价协同抑制浓度 多粘菌素配对，体外TOX和ADME，用于杀伤曲线，PK和MIC90选择多粘菌素配对和 类似物将在AIM 3中进行体内测试。 目的3(阶段2)在体内表征MedM类似物与所选增强剂的结合 建立相关小鼠抗体感染模型，鉴定铅系列结合产物。测试药效 高级药物类似物+多粘菌素增强剂抗PMBR抗体临床分离株在小鼠腹膜炎感染中的作用 建立小鼠大腿深部和中性粒细胞减少的肺部感染模型。在每项研究中，证明 如果与多粘菌素联合使用效果不佳，MedM类似物在统计学上有显著疗效(P&lt；0.05 用于联合产品的铅MedM系列的剂量识别。还将进行剂量分级研究。