New class of PBP inhibitors to address PBP2-mediated resistance in Neisseria gonorrhoeae

新型 PBP 抑制剂可解决淋病奈瑟菌 PBP2 介导的耐药性

基本信息

批准号：
10686113
负责人：
Denis Marc Daigle
金额：
$ 158.28万
依托单位：
VENATORX PHARMACEUTICALS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-05 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10686113
关键词：
Address Anti-Bacterial Agents Anti-Infective Agents Antibiotics Antigenic Variation Azithromycin Binding Biological Cefixime Ceftriaxone Cephalosporin Resistance Cephalosporins Chemicals Chlamydia trachomatis Clinical Clinical Research Contracts Crystallization Cyclic GMP Development Disease Notification Disease Outbreaks Dose Drug Kinetics Drug Targeting Epidemiology Escherichia coli Infections Evaluation Evolution Exhibits Failure Female Formulation Goals Gonorrhea In Vitro Incidence Infection Intramuscular Lactams Lead Link Maximum Tolerated Dose Mediating Medical Methods Microbiology Modeling Multi-Drug Resistance Mus Neisseria gonorrhoeae Oral Outpatients Penicillin Binding Protein 2 Penicillin-Binding Proteins Pharmaceutical Preparations Pharmacology Study Plants Preparation Process Property Qualifying Rattus Reporting Resistance Rodent Safety Septicemia Series Services South Carolina Structure Technology Transfer Testing Therapeutic Toxicology Universities Validation Variant analytical method antagonist appropriate dose bactericide beta-Lactamase beta-Lactams clinical candidate clinical development clinically relevant design drug development drug metabolism drug-resistant gonorrhea efficacy trial genotoxicity global health global health emergency improved in vivo indexing inhibitor lead optimization manufacture manufacturing organization method development mosaic mouse model new combination therapies novel novel therapeutics pharmacokinetics and pharmacodynamics pre-Investigational New Drug meeting pre-clinical preclinical development pressure prevent programs reproductive tract resistance frequency resistance mechanism synergism vaccine development

Address Anti-Bacterial Agents Anti-Infective Agents Antibiotics Antigenic Variation Azithromycin Binding Biological Cefixime Ceftriaxone Cephalosporin Resistance Cephalosporins Chemicals Chlamydia trachomatis Clinical Clinical Research Contracts Crystallization Cyclic GMP Development Disease Notification Disease Outbreaks Dose Drug Kinetics Drug Targeting Epidemiology Escherichia coli Infections Evaluation Evolution Exhibits Failure Female Formulation Goals Gonorrhea In Vitro Incidence Infection Intramuscular Lactams Lead Link Maximum Tolerated Dose Mediating Medical Methods Microbiology Modeling Multi-Drug Resistance Mus Neisseria gonorrhoeae Oral Outpatients Penicillin Binding Protein 2 Penicillin-Binding Proteins Pharmaceutical Preparations Pharmacology Study Plants Preparation Process Property Qualifying Rattus Reporting Resistance Rodent Safety Septicemia Series Services South Carolina Structure Technology Transfer Testing Therapeutic Toxicology Universities Validation Variant analytical method antagonist appropriate dose bactericide beta-Lactamase beta-Lactams clinical candidate clinical development clinically relevant design drug development drug metabolism drug-resistant gonorrhea efficacy trial genotoxicity global health global health emergency improved in vivo indexing inhibitor lead optimization manufacture manufacturing organization method development mosaic mouse model new combination therapies novel novel therapeutics pharmacokinetics and pharmacodynamics pre-Investigational New Drug meeting pre-clinical preclinical development pressure prevent programs reproductive tract resistance frequency resistance mechanism synergism vaccine development

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项目摘要

PROJECT SUMMARY Multidrug resistant-gonorrhea is a serious global health threat. Penicillin Binding Protein-targeting β-lactams have long been the front line therapeutic option for gonorrhea, but are now in serious jeopardy. Resistance to the last remaining front line β-lactams, the extended spectrum cephalosporins, has steadily increased over the past decades resulting in the CDC eliminating cefixime as a therapeutic option in 2012. Now only ceftriaxone remains, but a series of resistant clinical isolates exhibiting PBP2-target based resistance have emerged in the past decade, forecasting its imminent failure. As few clinical development candidates addressing MDR- gonorrhea are in the drug development pipeline, and vaccine development is unlikely to be a solution due to high antigenic variability in clinical isolates, there is an urgent need for new therapeutic options. A new chemical series maintaining PBP target inhibition represents a promising strategy, enabling new combination therapies to minimize further evolution of resistance. VenatoRx has identified a novel chemical series of reversible covalent non-β-lactam Penicillin Binding Protein inhibitors impervious to the action of β-lactamases that are being optimized to address altered PBP2 targets responsible for ESC-resistance in Neisseria gonorrhoeae. Significant strides in microbiological activity have been achieved with the lead compound VNRX-6355 in MDR-gonorrhea isolates including a mosaic PBP2-producing H041 clinical isolate. Improved binding to altered PBP2 variants by VNRX-6355 has provided a >128-fold improvement in microbiological activity in H041 over initial hit compounds in the series (shift in MIC from >512 mg/L to 4 mg/L) and is only 8-fold away from our MIC target to obtain an MIC90 of ≤0.5 mg/L. These compounds are highly selective, rapidly bactericidal and efficacious in a murine septicemia model of E. coli infection. The goal of this proposal is to select a potent preclinical candidate addressing PBP2 target variants in ESC-resistant gonorrhea, confirm favorable PK properties for intramuscular administration, select the first preclinical development candidate, perform preclinical IND-enabling studies and file an IND with the US FDA. Ultimately this approach is intended to be a long term strategy to safeguard PBP- targeting in gonorrhea treatment by preventing the expansion of β-lactamases in Neisseria gonorrhoeae that would inevitably evolve from more effective targeting of PBP2 variants by current or newly optimized β-lactam- based strategies.

项目摘要抗抗糖性巨型疾病是严重的全球健康威胁。青霉素结合蛋白靶向β-内酰胺长期以来一直是淋病的前线治疗选择，但现在处于严重危险之中。抵抗最后剩下的前线β-内酰胺是扩展的频谱头孢菌素，在过去的几十年导致CDC消除头孢菌症作为2012年的治疗选择。现在只有头孢曲松仍然存在，但是一系列具有PBP2目标抗性的抗性临床分离株已经出现在过去的十年，预测其即将失败。由于很少有人针对MDR-的临床发展候选者淋病是在药物开发管道中临床分离株中的抗原变异性，迫切需要新的治疗选择。一种新化学物质维持PBP目标抑制的系列是一种承诺策略，使新的组合疗法能够最小化抗性的进一步演变。 Venatorx已经确定了一系列新型的化学化学系列可逆共价非β-内酰胺青霉素结合蛋白抑制剂不受β-内酰胺酶的作用而不受欢迎优化以解决改变淋病奈瑟氏菌ESC抗性的改变的PBP2靶标。重要的 MDR-Gonorrhea中的铅化合物VNRX-6355已经实现了微生物活性的步伐分离株，包括产生H041的镶嵌PBP2临床分离株。改善了与改变的PBP2变体的结合 VNRX-6355与初始命中化合物相比，H041的微生物活性提高了> 128倍在系列中（MIC从> 512 mg/L到4 mg/L），距离我们的MIC目标仅8倍以获得 MIC90的≤0.5mg/l。这些化合物具有高度选择性，迅速的细菌且在鼠中有效大肠杆菌感染的败血病模型。该建议的目的是选择潜在的临床前候选人解决ESC耐药性淋病中的PBP2靶标变体，确认肌内的有利的PK特性管理，选择第一个临床前开发候选者，进行临床前的指定研究和向美国FDA提交IND。最终，这种方法旨在成为维护PBP-的长期战略通过防止在淋病中的β-内酰胺酶的扩张来靶向淋病治疗不可避免地会因通过电流或新优化的β-内酰胺 - 更有效地靶向PBP2变体基于策略。