Development of a novel agent to treat antimicrobial resistant Neisseria gonorrhoeae

开发治疗耐药性淋病奈瑟菌的新型药物

• 批准号: 9620389
• 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: 2018
• 资助国家: 美国
• 起止时间: 2018-06-15 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9620389
• 关键词: Active Sites; Address; Anabolism; Antimicrobial Resistance; Azithromycin; Bambermycins; Ceftriaxone; Cell Survival; Cell Wall; Centers for Disease Control and Prevention (U.S.); Cephalosporins; Chlamydia trachomatis; Clinical; Clinical Trials; Collaborations; Data; Development; Dose; Drug Kinetics; Escherichia coli; Exhibits; Female; Fermentation; Fluoroquinolones; Formulation; Foundations; Genitourinary system; Goals; Gonorrhea; Half-Life; HepG2; Human; In Vitro; Infection; Intramuscular; Intravenous; Ion Channel; Maps; Measures; Mediating; Methods; Microbiology; Modeling; Mus; Names; Natural Products; Neisseria gonorrhoeae; New Agents; Penicillin-Binding Proteins; Peptidoglycan; Pharmaceutical Preparations; Phase; Polymers; Reporting; Research; Resistance; Safety; Sampling; Septicemia; Sexually Transmitted Agents; Solid; Staphylococcus aureus; Tetracyclines; Therapeutic; Therapeutic Agents; Thigh structure; Time; Toxic effect; World Health Organization; analog; bactericide; base; beta-Lactams; clinical development; combat; crosslink; drug candidate; drug development; efficacy study; global health; in vivo; in vivo Model; inhibitor/antagonist; interest; moenomycin A; mutant; novel; novel therapeutics; pathogen; reproductive tract; resistance frequency; scale up; standard of care; subcutaneous; success; theories; transpeptidation

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.

世界卫生组织估计，全球每年有 7800 万人感染淋病。传播广泛 抗生素耐药性 Ng 的出现促使 CDC 将其指定为紧急威胁病原体。令人震惊的是， 目前，头孢曲松 (CRO) 的现有护理标准 (SOC) 双重疗法正在出现耐药性 和阿奇霉素（AZM）。尽管存在这场全球健康危机，但目前仍很少有新的治疗药物 治疗 AMR Ng 的临床开发。因此，具有新颖作用机制（MOA）的新药物不会交叉 需要对现有药物类别产生耐药性，并且本身不易受到快速耐药性选择的影响 解决 AMR Ng 的临床传播问题。我们的提案旨在开发一种新的 AMR NG 疗法，其具有新颖的 MOA 以前未在临床环境中用于治疗 GC，从而取代了 SOC 药物、CRO，并在 这样做可以解决 CRO 耐药性 Ng 的最严重威胁。我们最近发现了一种新颖且可申请专利的 天然产物默诺霉素 A (MoeA) 的类似物，我们命名为麦那霉素 (MedM)。而 β-内酰胺类如 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，可消除 PG 合成。 MedM 表现出色 活性（MIC范围，0.0005-0.004 ug/ml）与CRO相当，杀菌活性强，频率低 电阻 (FOR <1.14x10-9) 与 MoeA 类似。 MedM 还表现出有利的药代动力学特征， 突出特点是良好的皮下暴露和长半衰期，预计单剂量对抗 AMR- 吴。在坚实的初步数据基础上，我们的目标是： 目标 1（第一阶段；Ph1）。在 Ng 中建立 MedM MOA 并具有作为新型 GC 试剂的开发潜力。 里程碑 1. 获得 50 mg MedM 并直接在 Ng 中证明 MedM + AZM FICI < 4，MedM FOR < 1 x10-9，MedMR 突变体映射到 Ng PBP-TG 活性位点，25 个临床分离株的 MIC90 < 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。功效 POC 是通过 50% 的保护剂量（< 10 mg/kg）实现 4 天的存活。 目标 2（第 2 阶段；Ph2）。确定 MedM 对关键体内建模的适用性。 里程碑2.开发发酵提供0.5克MedM，证明MIC90等于或优于ETX0914 (< 0.25 ug/ml) 在 100 种不同的 AMR-Ng 临床分离株中，并使用经安全批准的配方确定配方 对于目标 3 中描述的体内功效模型，在相关物种中实现 10 倍 MIC90 暴露的载体。 目标 3（Ph2）。将 MedM 确立为治疗 GC 的候选药物。评估复合功效 在小鼠雌性淋球菌下生殖道感染（FGLGTI）和金黄色葡萄球菌大腿深部感染模型中。 里程碑 3. 证明 MedM 在 FGLGTI 模型中 5 天以内的 IM 治疗达到 100% 清除率 IM 治疗 24 小时内，小鼠大腿深部感染模型减少 >3 个对数。