Development of a novel agent to treat antimicrobial resistant Neisseria gonorrhoeae

世界卫生组织估计，全球每年有7800万人感染淋病。广泛传播 抗微生物耐药的Ng促使CDC将其指定为紧急威胁病原体。令人担忧的是， 目前对头孢曲松（CRO）的剩余现行标准治疗（SOC）双重治疗出现耐药性 和阿奇霉素（AZM）。尽管存在这一全球健康危机，但目前很少有新的治疗剂被用于治疗癌症。 治疗AMR Ng的临床开发。因此，具有新型作用机制（MOA）的新药物不会与 需要对现有药物类别具有抗性并且本身不容易受到快速抗性选择的影响， 解决AMR Ng的临床传播。我们的提案旨在开发一种新的AMR Ng治疗剂， MOA以前未在临床环境中用于治疗GC，从而取代SOC药物CRO， 这样做解决了抗CRO Ng的最严重威胁。我们最近发现了一种新的专利 天然产物默诺霉素A（MoeA）的类似物，我们命名为麦迪霉素（MedM）。而β-内酰胺类药物， CRO抑制青霉素结合蛋白（PBP）介导的肽聚糖（PG）聚合物的转肽作用，MedM 作为PBP转糖基化（TG）抑制剂，其消除PG合成。MedM显示出卓越的Ng 活性（MIC范围，0.0005-0.004 μ g/ml）与CRO相当，有效的杀菌活性，和低频率 电阻（FOR <1.14 × 10 -9）与MoeA相似。MedM还表现出有利的药代动力学特征， 突出表现为良好的皮下暴露和长半衰期，预期单次给药对AMR有效- Ng.在初步数据的坚实基础上，我们的目标是： 目标1（1期; Ph 1）。在Ng中建立MedM MOA，并将其开发为新型GC试剂。 里程碑1.获得50 mg MedM，并在Ng中直接证明MedM + AZM FICI < 4，MedM FOR <4， 1x 10 -9，MedMR突变体映射到Ng PBP-TG活性位点，并且在25个临床分离株中MIC 90 < 0.125 ug/ml。 可接受的体外毒性和最小的脱靶活性。建立体内模型的剂量范围。疗效 POC以有利于存活的50%保护剂量（< 10 mg/kg）达到4天。 目标2（第2阶段; Ph 2）。确定MedM适用于关键体内建模。 里程碑2.开发发酵以提供0.5 g MedM，证明MIC 90等于或优于ETX 0914的上级 25 ug/ml），并使用安全性批准的药物组合物鉴定制剂。 在相关种属中达到10 x MIC 90暴露的溶媒，用于目标3中描述的体内疗效模型。 目标3（Ph 2）。确立MedM作为治疗GC的候选药物开发。评价化合物疗效 在小鼠雌性淋球菌下生殖道感染（FGLGTI）和S.金黄色葡萄球菌大腿深部感染模型。 里程碑3.证明在24小时IM治疗内，MedM在FGLGTI模型中实现100%清除< 5 days IM treatment and >，在鼠大腿深部感染模型中减少3个对数。

The WHO estimates gonorrhea infections occur in 78 million people globally every year. The extensive spread of antimicrobial resistant Ng has prompted the CDC to designate it as an Urgent Threat pathogen. Alarmingly, resistance is now emerging to the remaining current standard of care (SOC) dual therapy of ceftriaxone (CRO) and azithromycin (AZM). Despite this global health crisis, few new therapeutic agents are currently under clinical development to treat AMR Ng. Thus, new agents with novel mechanisms of action (MOA) not cross resistant to existing drug classes and not themselves susceptible to rapid resistance selection are needed to address the clinical spread of AMR Ng. Our proposal aims to develop a new AMR Ng therapeutic with a novel MOA not previously exploited in a clinical setting to treat GC, thereby replacing the SOC agent, CRO, and in doing so address the most serious threat of CRO-resistant Ng. We recently identified a novel and patentable analog of the natural product Moenomycin A (MoeA), we name Medinamycin (MedM). Whereas β-lactams like CRO inhibit penicillin binding protein (PBP)-mediated transpeptidation of peptidoglycan (PG) polymers, MedM acts as a PBP transglycosylation (TG) inhibitor that abolishes PG synthesis. MedM displays exceptional Ng activity (MIC range, 0.0005-0.004 ug/ml) comparable to CRO, potent bactericidal activity, and a low frequency of resistance (FOR <1.14x10-9) similar to MoeA. MedM also exhibits an advantageous pharmacokinetic profile, highlighted by good subcutaneous exposure and long half-life anticipating single dose efficacy against AMR- Ng. Building upon a solid foundation of preliminary data, our Aims are: Aim 1 (Phase 1; Ph1). Establish MedM MOA in Ng and development potential as a novel GC agent. Milestone 1. Obtain 50 mg of MedM and demonstrate directly in Ng that MedM + AZM FICI < 4, MedM FOR < 1 x10-9, MedMR mutants map to Ng PBP-TG active site, and MIC90 < 0.125 ug/ml across 25 clinical isolates. Acceptable in vitro toxicity and minimal off-target activity. Establish dose-ranging for in vivo models. Efficacy POC is achieved with favorable 50% protective dose for survival (< 10 mg/kg) for 4 days. Aim 2 (Phase 2; Ph2). Establish MedM suitability for critical in vivo modeling. Milestone 2. Develop fermentation to provide 0.5 g MedM, demonstrate MIC90 equal or superior to ETX0914 (< 0.25 ug/ml) in 100 diverse AMR-Ng clinical isolates, and identify a formulation using a safety approved vehicle that achieves 10x MIC90 exposure in relevant species for in vivo efficacy models described in Aim 3. Aim 3 (Ph2). Establish MedM as a drug development candidate to treat GC. Evaluate compound efficacy in a murine female gonococcal lower genital tract infection (FGLGTI) and S. aureus deep thigh infection model. Milestone 3. Demonstrate that MedM achieves 100% clearance in FGLGTI models < 5 days IM treatment and >3 log reduction in murine deep thigh infection model within 24 h IM treatment.