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: 10400905
• 负责人: Steven Armen Boyd
• 金额: $ 118.32万
• 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/10400905
• 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; antagonist; 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; innovation; lead optimization; lead series; meetings; method development; novel; novel antibiotic class; 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.

项目摘要 在过去的十年中，肠杆菌目的碳青霉烯类耐药性稳步增加，导致多药耐药。 和泛耐药（MDR/PDR），进一步强调了对新的创新疗法的需求。碳青霉烯- 耐药肠球菌（CRE）是一个严重的全球性健康问题，由美国疾病中心分类 控制和预防被列为“紧急威胁”，并被世界卫生组织列为“第一优先严重威胁”。 β-内酰胺类药物长期以来一直是此类感染的一线治疗选择，但这些药物的疗效， 包括最后的手段碳青霉烯类，受到最近β-内酰胺酶（特别是亚型）扩张的威胁 (e.g., NDM）在不受临床可用β-内酰胺/β-内酰胺影响的肠球菌目中迅速传播。 内酰胺酶抑制剂组合。为了满足医疗需求，Venatorx已经确定了一系列新颖的高度 结合并破坏青霉素结合蛋白（PBP）转肽酶（TBP）的选择性环状硼酸盐 功能，同时避免所有当前和未来的β-内酰胺酶的作用。这种方法创建了第一个前景 和“罕见的”新型革兰氏阴性菌制剂，用于治疗由任何产生β-内酰胺酶的CRE引起的感染 病原体微生物活性的重大进展已经在该系列中取得了领先地位， 化合物VNRX-6736，MIC 90为32 µg/mL，相对于美罗培南-戊硼巴坦的128 µg/mL， 在最近的100株CRE分离株挑战集中，头孢他啶-阿维巴坦≥ 1，024 µg/mL。不仅VNRX- 从MIC 90角度来看，6736优于这些临床对照药物，但MIC范围较窄 由于避免了β-内酰胺酶，这一特征最终将有利于断点的设置。该系列迅速 杀菌，表现出较低的自发突变频率（在4x MIC下的抗性频率<2.7 x 10-11 在大肠coli ATCC 25922），并具有良好的ADME和PK性质。已实现概念有效性验证 VNRX-6736在碳青霉烯类耐药E.大肠杆菌感染与药代动力学 建模表明，需要高于MIC 30-45%的时间才能达到功效。拟议的优化工作 本文目标是通过合理的结构导向设计来驱动抗菌活性的8倍改进， 改善PBP结合相互作用动力学，使MIC 90 ≤ 4 µg/mL。这种优化的环状硼酸酯PBPi 可能是第一类解决β-内酰胺类耐药性的新型抗生素，用于治疗由以下原因引起的感染： CRE和肠球菌耐药性发展的长期治疗方案。