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

基本信息

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
项目类别：
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

项目摘要

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.

世卫组织估计每年全球7800万人发生淋病感染。广泛的传播抗菌素抗药性NG促使疾病预防控制中心将其指定为紧急威胁病原体。令人震惊的是现在，抵抗力正在出现到头孢曲松（CRO）的剩余当前护理标准（SOC）双重治疗和阿奇霉素（AZM）。尽管发生了全球健康危机，但目前很少有新的治疗剂治疗AMR NG的临床发展。那是具有新型作用机理（MOA）的新代理商不交叉的对现有药物类别有抵抗力，而不容易选择快速抵抗的选择解决AMR NG的临床扩散。我们的建议旨在通过小说开发一种新的AMR NG疗法 MOA以前未在临床环境中探索以治疗GC，从而取代SOC代理，CRO和IN 这样做解决了最严重的耐药Ng威胁。我们最近确定了一部小说和可申请的小说天然产物Moenomycin A（MOEA）的类似物，我们命名Medinamycin（MEDM）。而β-内酰胺也喜欢 CRO抑制青霉素结合蛋白（PBP）介导的Pepperidoglycan（PG）聚合物，MEDM的转肽充当废除PG合成的PBP转糖基化（TG）抑制剂。 MEDM显示出色的NG 活动（MIC范围，0.0005-0.004 ug/ml）可与CRO相当，潜在的生物学活性和低频与MOEA相似的电阻（<1.14x10-9）。 MEDM还表现出有利的药代动力学特征，以良好的皮下暴露和长期的半衰期预期，预期单剂量效率 ng。我们的目的是以扎实的初步数据为基础：目标1（阶段1; PH1）。在NG和开发潜力中建立MEDM MOA作为新型GC代理。里程碑1。获得50毫克的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，MIC90 <0.125 ug/ml在25个临床分离株中。可以接受的体外毒性和最少的脱靶活动。为体内模型建立剂量范围。功效 POC以50％的保护剂量可实现生存期（<10 mg/kg）4天。 AIM 2（阶段2; PH2）。建立MEDM适合体内建模的适用性。里程碑2。开发发酵以提供0.5 g MedM，证明MIC90等于或优于ETX0914 （<0.25 ug/ml）在100条潜水员AMR-NG临床分离株中，并使用安全批准的公式识别公式在AIM 3中描述的体内效率模型中，在相关物种中实现10倍MIC90暴露的车辆。目标3（ph2）。建立MEDM作为治疗GC的药物开发候选者。评估复合效率在鼠雌性淋球菌下生殖道感染（FGLGTI）和金黄色葡萄球菌深大腿感染模型中。里程碑3。证明MEDM在FGLGTI模型中达到100％的间隙<5天IM治疗和在24小时IM治疗中，> 3鼠深大腿感染模型的对数减少。