Novel cyclic boronate Penicillin Binding Protein Inhibitors to eliminate the threat posed by β-lactamases and enable a future treatment option for carbapenem-resistant Enterobacterales infections

新型环状硼酸青霉素结合蛋白抑制剂可消除β-内酰胺酶造成的威胁，并为碳青霉烯类耐药肠杆菌感染提供未来的治疗选择

• 批准号: 10215763
• 负责人: Steven Armen Boyd
• 金额: $ 148.32万
• 依托单位: VENATORX PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-04 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10215763
• 关键词: Address; Anti-Bacterial Agents; Antibiotics; Binding; Binding Proteins; Canada; Carbapenems; Ceftazidime; Centers for Disease Control and Prevention (U.S.); Clinical; Clinical Research; Contracts; Cyclic GMP; Development; Dose; Drug Kinetics; Drug resistance; Enteral; Escherichia coli; Escherichia coli Infections; Evaluation; Evolution; Exhibits; Formulation; Frequencies; Future; Gram-Negative Bacteria; Health care facility; Hospitals; Imipenem; In Vitro; Infection; Innovative Therapy; Intravenous; Kinetics; Lactams; Lead; Maximum Tolerated Dose; Medical; Meropenem; Methods; Microbiology; Modeling; Mus; Mutation; Patients; Penicillin-Binding Proteins; Peptidyltransferase; Periodicity; Pharmaceutical Preparations; Pharmacology; Plants; Preparation; Problem Solving; Process; Property; Rattus; Refractory; Research Design; Resistance; Resistance development; Resort; Rodent; Safety; Series; Serine; Structure; Study models; Technology Transfer; Therapeutic; Thigh structure; Time; Toxicology; Validation; World Health Organization; analytical method; appropriate dose; austin; bactericide; base; beta-Lactam Resistance; beta-Lactamase; beta-Lactams; carbapenem resistance; clinical candidate; design; drug metabolism; genotoxicity; global health; improved; in vivo; inhibitor/antagonist; innovation; lead optimization; lead series; meetings; method development; novel; pathogen; pharmacokinetic model; pharmacokinetics and pharmacodynamics; pre-clinical; preclinical development; preclinical study; programs; resistance frequency; resistance mechanism; safety assessment; synergism; targeted agent

PROJECT SUMMARY Carbapenem-resistance in Enterobacterales has steadily increased over the past decade, leading to multidrug and pan-drug resistance (MDR/PDR), further emphasizing the need for new innovative therapies. Carbapenem- resistant Enterobacterales (CRE) is a serious global health problem classified by the US Centers for Disease Control and Prevention as an “Urgent threat” and by the World Health Organization as a “Priority 1 critical threat”. The β-lactams have long been the front line therapeutic option for such infections, but efficacy of these agents, including last resort carbapenems, is threatened by recent expansion of β-lactamases, particularly subtypes (e.g., NDM) spreading rapidly among Enterobacterales that are unaffected by clinically-available β-lactam/β- lactamase inhibitor combinations. To address the medical need, Venatorx has identified a novel series of highly selective cyclic boronates that bind to and disrupt penicillin-binding protein (PBP) transpeptidase (TPase) function while avoiding the action of all current and future β-lactamases. This approach creates the first prospect and “rare” new class gram negative agent to treat infections caused by any β-lactamase-producing CRE pathogen. Significant strides in microbiological activity have already been achieved within the series by the lead compound VNRX-6736, with an MIC90 of 32 µg/mL relative to 128 µg/mL for meropenem-vaborbactam and ≥1,024 µg/mL for ceftazidime-avibactam in a recent challenge set of 100 CRE isolates. Not only does VNRX- 6736 outperform these clinical comparators from an MIC90 perspective, but does so with a narrow range of MIC owing to β-lactamase avoidance, a feature that will ultimately benefit setting of breakpoints. The series is rapidly bactericidal, exhibits a low spontaneous mutational frequency (frequency of resistance at 4x MIC of <2.7 x 10-11 in E. coli ATCC 25922) and has favorable ADME and PK properties. Proof of concept efficacy has been achieved by VNRX-6736 in the murine thigh model of carbapenem-resistant E. coli infection and pharmacokinetics modeling suggests that 30-45% time above MIC is required to achieve efficacy. Optimization efforts proposed herein are targeting an 8-fold improvement in antibacterial activity driven by rational structure-guided design to improve PBP binding interaction kinetics to enable an MIC90 ≤ 4 µg/mL. Such an optimized cyclic boronate PBPi could be a 1st new class antibiotic addressing resistance to β-lactams for the treatment of infections caused by CRE and a long term therapeutic solution to resistance development in Enterobacterales.

项目总结 肠杆菌科细菌对碳青霉烯类抗生素的耐药性在过去十年中稳步增加，导致了多药耐药 和泛耐药(MDR/PDR)，进一步强调了新的创新疗法的必要性。碳青霉烯- 耐药肠杆菌(CRE)是美国疾病中心归类的一个严重的全球健康问题 控制和预防被列为“紧急威胁”，并被世界卫生组织列为“优先1重大威胁”。 长期以来，β-内酰胺类药物一直是此类感染的一线治疗选择，但这些药物的疗效， 包括最后的碳青霉烯类在内的β-内酰胺酶最近的扩张，特别是亚型，正受到威胁 (例如，NDM)在临床可用β-内酰胺/β-不影响的肠杆菌属中迅速传播- 内酰胺酶抑制剂组合。为了满足医疗需求，Venatorx已经确定了一系列高度 与青霉素结合蛋白(PBP)转肽酶(TPase)结合并破坏的选择性环状硼酸盐 发挥作用，同时避免所有当前和未来的β-内酰胺酶的作用。这种方法创造了第一个前景 以及治疗任何产β-内酰胺酶Cre引起的感染的罕见的新型革兰氏阴性药 病原体。在这一系列活动中，领先者已经在微生物活动方面取得了重大进展 化合物VNRX-6736，其MIC90为32微克/毫升，而美罗培南-瓦博巴坦为128微克/毫升； 在最近的一组100Cre分离株的挑战中，≥为1,024微克/毫升头孢他啶-阿维巴坦。不仅VNRX- 从MIC90的角度来看，6736的表现优于这些临床比较器，但MIC范围较小 由于避免了β-内酰胺酶，这一功能最终将有利于断点的设置。这一系列节目进展迅速。 杀菌，表现出较低的自发突变频率(在4倍MIC时的抗药性频率为-lt；2.7 x 10-11 在E.ColiATCC 25922中)，并具有良好的ADME和PK性质。已实现概念验证效果 VNRX-6736在小鼠大腿碳青霉烯耐药大肠杆菌感染模型中的应用及药代动力学研究 模拟表明，达到药效需要30%-45%的MIC以上时间。建议的优化工作 在此，我们的目标是通过合理的结构指导设计将抗菌活性提高8倍 改进多酚结合相互作用动力学，使MIC90≤达到4微克/毫升。这样一种优化的环状硼酸盐PBPI 可能成为解决对β-内酰胺类抗生素耐药性的第一类新抗生素，用于治疗由 CRE和肠杆菌属耐药性发展的长期治疗解决方案。