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。广泛的传播 抗菌素耐药Ng的出现促使疾控中心将其列为紧急威胁病原体。令人震惊的是， 目前尚存的头孢曲松(CRO)双重疗法(SOC)出现耐药性。 和阿奇霉素(Azm)。尽管出现了这场全球健康危机，但目前几乎没有新的治疗药物 治疗AMR Ng的临床进展。因此，具有新作用机制(MOA)的新试剂不会交叉 需要对现有药物类别具有抗药性，并且本身不对快速抗药性选择敏感 解决AMR Ng的临床传播问题。我们的建议旨在开发一种新的AMR Ng疗法和一种新的 MOA以前没有在临床环境中用于治疗GC，从而取代了SOC试剂、CRO和 这样做解决了最严重的抗CRO Ng威胁。我们最近发现了一种新颖的、可申请专利的 天然产物莫诺霉素A(MOEA)的类似物，我们称其为麦迪霉素(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)聚合物转肽 作为一种PBP转糖基化(TG)抑制剂，取消PG的合成。MedM显示异常的NG 最低抑菌浓度范围：0.0005-0.004微克/毫升，杀菌活性强，频率低 与MOEA类似的抗性(对于1.14×10-9)。MedM还表现出有利的药代动力学特征， 突出的特点是良好的皮下暴露和较长的半衰期，预计单次给药对AMR- Ng.在坚实的初步数据基础上，我们的目标是： 目标1(阶段1；PH1)。Ng中MedM MOA的建立及其作为一种新型GC试剂的开发潜力。 里程碑1.获得50毫克的MedM，并在Ng中直接证明MedM+Azm Figi；4，MedM for&lt； 25株临床分离株的MIC90和MIC90分别为1×10-9和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 以50%的保护剂量(&lt；10 mg/kg)连续4天获得POC。 目标2(阶段2；PH2)。建立关键的活体建模的MedM适合性。 里程碑2.开发发酵提供0.5g MedM，证明MIC90等于或优于ETX0914 (&lt；0.25 ug/ml)在100种不同的AMR-Ng临床分离株中，并使用安全批准的 在目标3中描述的体内药效模型中，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。评价复方药效 在小鼠女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模型和5天IM治疗中达到100%清除 &gt；3小鼠大腿深部感染模型中肌注治疗24小时内LOG减少。