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

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， 包括碳青霉烯类抗生素，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 病原体在微生物活性方面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），具有良好的ADME和PK特性。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。

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.