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：
10459332
负责人：
Denis Marc Daigle
金额：
$ 157.98万
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/10459332
关键词：
Address Anti-Bacterial Agents Anti-Infective Agents Antibiotics Antigenic Variation Azithromycin Binding Cefixime Ceftriaxone Centers for Disease Control and Prevention (U.S.)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 Lead Link Maximum Tolerated Dose Mediating Medical Methods Microbiology Modeling Mosaicism Multi-Drug Resistance Mus Neisseria gonorrhoeae Oral Outpatients Penicillin Binding Protein 2 Penicillin-Binding Proteins Pharmaceutical Preparations Pharmacology Study Plants Preparation Process Property 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 base beta-Lactamase beta-Lactams clinical candidate clinical development clinically relevant design drug development drug metabolism efficacy trial genotoxicity global health global health emergency improved in vivo indexing inhibitor lead optimization meetings method development mouse model new combination therapies novel novel therapeutics pharmacokinetics and pharmacodynamics pre-clinical preclinical development pressure prevent programs reproductive tract resistance frequency resistance mechanism synergism vaccine development

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.

项目概要多重耐药性淋病是一种严重的全球健康威胁。长期以来一直是淋病的一线治疗选择，但现在面临着严重的耐药性。最后剩下的前线β-内酰胺类药物，即广谱头孢菌素，在过去几年中稳步增长几十年过去了，导致 CDC 在 2012 年取消了头孢克肟作为治疗选择。现在只有头孢曲松仍然存在，但一系列表现出基于 PBP2 靶点耐药性的耐药临床分离株已经在过去十年，预测其即将失败，因为很少有临床开发候选药物能够解决 MDR-问题。淋病正在药物开发过程中，由于高风险，疫苗开发不太可能成为解决方案由于临床分离株的抗原变异性，迫切需要新的治疗选择。系列维持 PBP 目标抑制代表了一种有前途的策略，使新的联合疗法能够 VenatoRx 已确定了一种新型可逆共价化学系列。非β-内酰胺青霉素结合蛋白抑制剂不受β-内酰胺酶的作用优化以解决导致淋病奈瑟氏菌耐药的 PBP2 靶标的改变。先导化合物 VNRX-6355 在耐多药淋病中的微生物活性方面取得了长足进步分离株，包括产生嵌合 PBP2 的 H041 临床分离株，通过改善与改变的 PBP2 变体的结合。 VNRX-6355 使 H041 中的微生物活性比初始化合物提高了 128 倍以上在该系列中（MIC 从 >512 mg/L 转变为 4 mg/L），距离我们的 MIC 目标仅 8 倍，以获得这些化合物的 MIC90 ≤0.5 mg/L，具有高选择性、快速杀菌作用，对小鼠有效。大肠杆菌感染的败血症模型该提案的目标是选择有效的临床前候选药物。解决 ESC 耐药性淋病中的 PBP2 靶点变异，确认肌内注射的有利 PK 特性管理，选择第一个临床前开发候选人，进行临床前 IND 支持研究和最终，这种方法旨在成为保护 PBP 的长期策略。通过阻止淋病奈瑟菌中 β-内酰胺酶的扩增来靶向治疗淋病不可避免地会从当前或新优化的 β-内酰胺更有效地靶向 PBP2 变体中演变而来为基础的策略。