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

• 批准号: 10228592
• 负责人: Denis Marc Daigle
• 金额: $ 144.11万
• 依托单位: VENATORX PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 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/10228592
• 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; 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/antagonist; 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

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.

项目总结