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

鲍曼不动杆菌（Ab）和相关菌种。引起严重的院内感染性肺炎，伤口，血液和尿液 肠道感染，死亡率为25- 75%。多药耐药（MDR）抗体的出现 分离株使其难以用大多数标准护理抗生素治疗。碳青霉烯类已成为 然而，治疗Ab感染的首选疗法，现在超过50%的感染是碳青霉烯类耐药Ab （螃蟹）。因此，WHO和CDC将CRAB列为优先级-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CRAB的最后手段， 由于潜在的肾毒性，其治疗指数较低。为了满足这一未得到满足的医疗需求，我们的目标是 开发一种有效的组合剂，其包含多粘菌素增效剂和有效的、机械上 新抗生素麦迪霉素（MedM）。MedM不受临床相关抗生素耐药性模式的影响， 表现出低FOR并提供针对Ab的强协同杀菌活性，包括粘菌素抗性， MDR和CRAB分离株，并被预测为安全有效的抗生素，以允许较低的有效剂量， PMB，从而减少不良影响。 目的1（第1阶段）验证开发有效的半合成MedM类似物的可行性， 与PMB和/或SPR 741组合对抗多粘菌素R Ab。改进MedM生物工艺， Aim 1研究。证明化学品的可处理性。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测定类似物。证明a的体内功效 MedM类似物+ PMB在鼠菌血症感染模型中针对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优化， 目的是鉴定具有改善的效力和/或药物样性质的MedM类似物。增加可靠性 使用20 L生物反应器将MedM生产水平提高至>250 mg/L，最终生产30 g MedM。使用此 材料，根据新兴的SAR以迭代方式制备多达150种半合成类似物。测量 所有化合物的Ab MIC和选定化合物的Ab MIC评价协同抑制浓度， 多粘菌素配偶体、体外毒性和ADME、FOR、杀伤曲线、PK和MIC 90，以选择多粘菌素配偶体， 类似物推进到目标3中的体内测试。 目的3（第2阶段）MedM类似物与所选增效剂组合的体内表征 相关小鼠Ab感染模型，以鉴定先导系列组合产品。测试功效 上级MedM类似物+多粘菌素增效剂在小鼠腹膜炎感染中对抗PMBR Ab临床分离株 模型，然后是深大腿和贫血小鼠肺部感染模型。在每项研究中，证明 如果与多粘菌素以亚有效浓度组合，MedM类似物提供统计学显著的功效（P < 0.05）。 剂量，以确定组合产品的主要MedM系列。还将进行剂量分次研究。

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.