New class of PBP inhibitors to address PBP2-mediated resistance in Neisseria gonorrhoeae

项目摘要 多重耐药淋病是一个严重的全球性健康威胁。青霉素结合蛋白靶向β-内酰胺类药物 长期以来一直是淋病的一线治疗选择，但现在正处于严重的危险之中。抗 最后剩下的一线β-内酰胺类药物，即超广谱头孢菌素类药物， 在过去的几十年中，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，但在美国已经出现了一系列表现出基于PBP 2靶标的耐药性的耐药临床分离株。 过去十年，预测其即将失败。由于解决MDR的临床开发候选药物很少， 淋病是在药物开发管道，疫苗的发展是不太可能的解决方案，由于高 由于临床分离株中存在抗原变异，因此迫切需要新的治疗选择。一种新的化学 系列维持PBP靶向抑制代表了一种有前途的策略，使新的联合疗法， 最大限度地减少耐药性的进一步发展。VenatoRx已经确定了一种新的化学系列的可逆共价键， 不受β-内酰胺酶作用的非β-内酰胺青霉素结合蛋白抑制剂， 优化以解决淋病奈瑟菌中负责ESC抗性的改变的PBP 2靶标。显著 在MDR淋病中，先导化合物VNRX-6355在微生物活性方面取得了长足进步 分离株，包括产生嵌合PBP 2的H 041临床分离株。通过以下方式改善与改变的PBP 2变体的结合： VNRX-6355在H 041中的微生物活性比初始命中化合物提高了>128倍 在该系列中（MIC从>512 mg/L变为4 mg/L），并且距离我们的MIC目标仅8倍，以获得 MIC90 ≤0.5 mg/L。这些化合物在小鼠中具有高度选择性、快速杀菌和有效性。 E.大肠杆菌感染。该提案的目标是选择一种有效的临床前候选药物 解决ESC耐药淋病中的PBP 2靶向变体，证实肌内给药的有利PK特性 管理，选择第一个临床前开发候选药物，进行临床前IND使能研究， 向美国FDA提交IND。最终，这种方法旨在成为保护PBP的长期战略- 通过防止淋病奈瑟菌中β-内酰胺酶的扩增， 将不可避免地从当前或新优化的β-内酰胺酶更有效地靶向PBP 2变体演变而来， 基于战略。

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.