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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：
9913150
负责人：
Terry Roemer
金额：
$ 95.3万
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 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9913150
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 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 human pathogen 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.

世界卫生组织估计，全球每年有7800万人感染淋病。广泛传播