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; 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.

ACINETOBACTER BAUMANNII（AB）和相关的spp。引起严重的医院肺炎，伤口，血液和尿 道感染，死亡率范围为25-75％。多药（MDR）AB的出现 分离株使用大多数护理标准抗生素治疗变得困难。碳青霉烯已成为 然而，首选治疗AB感染的疗法，现在超过50％的感染是抗碳青霉烯的AB （螃蟹）。因此，世卫组织和疾病预防控制中心将螃蟹归类为优先级至关重要和紧急 威胁病原体。多霉菌素B（PMB）和colistin已成为最后一种治疗螃蟹的抗生素 由于潜在的肾毒性，它们的治疗指数低。为了满足这种未满足的医疗需求，我们的目标是 开发一个有效的组合剂 新颖的抗生素，medinamycin（MEDM）。 MEDM不受临床相关抗生素耐药性的影响， 表现出低的表现，并提供针对AB的强大协同杀菌活性，包括抗co菌素 MDR和CRAB分离株，预计将是一种安全有效的抗生素，可允许较低的有效剂量 PMB，从而减少不良影响。 AIM 1（阶段1）验证开发有效的半合成MedM类似物的可行性 与PMB和/或SPR741结合使用Polymyxinr AB。改善MedM生物处理以交付> 1 g AIM 1研究。证明化学障碍。发展新的结构活动关系（SAR） 使用MOA进行微生物活性和细胞毒性测定的类似物。证明了一个体内功效 MEDM模拟 + PMB针对鼠类菌血症感染模型中的PMBR AB分离物。 AIM 2（阶段2）完整的生物过程优化，并与 鉴定具有改善效力和/或药物（例如特性）的MEDM类似物的目的。增加可靠 使用20L生物反应器的MEDM生产水平至> 250 mg/L，最终产生30 g MEDM。使用此 材料，根据新兴的SAR，以迭代方式准备多达150种半合成类似物。措施 所有化合物的AB MIC，对于精选化合物，可以评估具有潜力的协同抑制浓度 多霉菌蛋白伴侣，体外TOX和ADME，因为杀死曲线，PK和MIC90，以选择多氧化物伴侣和 在AIM 3中进行类似物进行体内测试。 AIM 3（第2阶段）在体内表征MedM类似物与选定的增强剂组合在体内表征 相关的AB感染的小鼠模型以识别铅系列组合产品。测试功效 小鼠腹膜炎感染中针对PMBR AB临床分离株的上级MEDM类似物 +多性淋巴细胞增强剂 模型，然后是大腿和中性粒细胞减少小鼠肺部感染模型。在每项研究中，证明 如果在亚效率下与多粘蛋白结合使用MEDM类似物，则具有统计学意义的功效（P <0.05） 剂量以识别组合产品的铅MedM系列。还将进行剂量分馏研究。