Uehara Tsuyoshi, Zulli Allison L, Miller Brittany, Avery Lindsay M, Boyd Steven A, Chatwin Cassandra L, Chu Guo-Hua, Drager Anthony S, Edwards Mitchell, Emeigh Hart Susan G, Myers Cullen L, Rongala Gopinath, Stevenson Annie, Uehara Kyoko, Yi Fan, Wang Bibo, Liu Zhenwu, Wang Mingyue, Zhao Zhichao, Zhou Xinming, Zhao Haiyan, Stratton Caleb M, Bala Sandeepchowdary, Davies Christopher, Tkavc Rok, Jerse Ann E, Pevear Daniel C, Burns Christopher J, Daigle Denis M, Condon Stephen M
Venatorx Pharmaceuticals, Inc., Malvern, PA, USA.
BioDuro-Sundia, Beijing, China.
bioRxiv. 2024 Dec 27:2024.12.27.630553. doi: 10.1101/2024.12.27.630553.
β-Lactams are the most widely used antibiotics for the treatment of bacterial infections because of their proven track record of safety and efficacy. However, susceptibility to β-lactam antibiotics is continually eroded by resistance mechanisms. Emerging multidrug-resistant (MDR) strains possessing altered alleles (encoding PBP2) pose a global health emergency as they threaten the utility of ceftriaxone, the last remaining outpatient antibiotic. Here we disclose a novel benzoxaborinine-based penicillin-binding protein inhibitor series (boro-PBPi) that is envisioned to address mediated resistance while offering protection against evolution and expansion of β-lactamases. Optimization of boro-PBPi led to the identification of compound (VNRX-14079) that exhibits potent antibacterial activity against MDR achieved by high affinity binding to the PBP2 target. Boro-PBPi/PBP2 complex structures confirmed covalent interaction of the boron atom with Ser310 and the importance of the β-β loop for improved affinity. elicits bactericidal activity, a low frequency of resistance, a good safety profile, suitable pharmacokinetic properties, and in vivo efficacy in a murine infection model against ceftriaxone-resistant . is a promising anti-gonorrhea agent poised for further advancement.
β-内酰胺类抗生素因其已被证实的安全性和有效性记录，是治疗细菌感染最广泛使用的抗生素。然而，β-内酰胺类抗生素的敏感性不断受到耐药机制的侵蚀。出现的具有改变等位基因（编码PBP2）的多重耐药（MDR）菌株构成了全球卫生紧急情况，因为它们威胁到最后一种剩余的门诊用抗生素头孢曲松的效用。在此，我们披露了一种基于苯并硼恶嗪的新型青霉素结合蛋白抑制剂系列（硼-PBPi），预计该系列可解决介导的耐药性问题，同时提供针对β-内酰胺酶进化和扩展的保护。硼-PBPi的优化导致鉴定出化合物（VNRX-14079），该化合物通过与PBP2靶点的高亲和力结合，对MDR表现出强大的抗菌活性。硼-PBPi/PBP2复合物结构证实了硼原子与Ser310的共价相互作用以及β-β环对提高亲和力的重要性。在针对头孢曲松耐药的小鼠感染模型中，其具有杀菌活性、低耐药频率、良好的安全性、合适的药代动力学特性以及体内疗效。它是一种有前景的抗淋病药物，有望进一步发展。
