Shin Eunjeong, Taracila Magdalena A, Quan Pojun, Khan Md Mahbub Kabir, Cox Jonathan, Patel Diya, Dousa Khalid M, Parmar Aetan, Nantongo Mary, Nguyen David C, Rubin Eric J, Holland Steven M, Kreiswirth Barry N, Buynak John D, Bonomo Robert A
Louis Stokes Cleveland VA Medical Center, Case Western Reserve University, Cleveland, Ohio, USA.
Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
Antimicrob Agents Chemother. 2025 Aug 6;69(8):e0017025. doi: 10.1128/aac.00170-25. Epub 2025 Jun 17.
() poses significant clinical challenges and underscores the urgent need for safer and more effective treatments, including β-lactams. Among currently available carbapenems, imipenem is widely used to treat infections by combining with other antibiotics. Commercial carbapenems share a common scaffold with C2 modifications, whereas this study focuses on novel carbapenem candidates with C5α modifications. We evaluated their antibacterial activity against ATCC 19977 and clinical isolates, as well as their acylation of peptidoglycan target receptors (L,D-transpeptidases [LDTs] and penicillin-binding proteins [PBPs]) and the β-lactamase enzyme Bla. studies of two C5α-modified carbapenems, JDB/NA-1-157 and JDB/NA-1-208, revealed distinct antibacterial effects. JDB/NA-1-157 demonstrated potent bacterial killing with low minimum inhibitory concentrations (MICs; 0.125-8 mg/L) and near-complete eradication within 5 days, surpassing the efficacy of the standard-of-care regimen (amikacin + clarithromycin + imipenem). In contrast, JDB/NA-1-208 exhibited poor bacterial killing, with high MICs (16-256 mg/L) and limited efficacy in time-kill studies. However, JDB/NA-1-208 showed synergistic killing when combined with other β-lactams. Mechanistically, JDB/NA-1-208 is not a substrate for Bla, while JDB/NA-1-157 is, albeit with low catalytic efficiency. This is supported by the observation that the addition of avibactam did not enhance synergy with JDB/NA-1-157. The substantial bacterial killing effect of JDB/NA-1-157 is attributed to its high binding affinity for PBP-B, PBP-lipo, PonA2, D,D-carboxypeptidase, and LDT1-2. These findings highlight the potential of novel C5α-modified carbapenems, particularly JDB/NA-1-157, as promising therapeutic candidates for infections.
（）带来了重大的临床挑战，并突出了对包括β-内酰胺类在内的更安全、更有效治疗方法的迫切需求。在目前可用的碳青霉烯类药物中，亚胺培南通过与其他抗生素联合使用，被广泛用于治疗感染。商业化的碳青霉烯类药物具有带有C2修饰的共同骨架，而本研究聚焦于具有C5α修饰的新型碳青霉烯类候选药物。我们评估了它们对ATCC 19977和临床分离株的抗菌活性，以及它们对肽聚糖靶标受体（L，D-转肽酶[LDTs]和青霉素结合蛋白[PBPs]）和β-内酰胺酶Bla的酰化作用。对两种C5α修饰的碳青霉烯类药物JDB/NA-1-157和JDB/NA-1-208的研究揭示了不同的抗菌效果。JDB/NA-1-157表现出强大的细菌杀伤作用，最低抑菌浓度（MICs；0.125 - 8 mg/L）较低，且在5天内几乎完全根除，超过了标准治疗方案（阿米卡星 + 克拉霉素 + 亚胺培南）的疗效。相比之下，JDB/NA-1-208表现出较差的细菌杀伤效果，MICs较高（16 - 256 mg/L），在时间杀菌研究中的疗效有限。然而，JDB/NA-1-208与其他β-内酰胺类药物联合使用时表现出协同杀伤作用。从机制上讲，JDB/NA-1-208不是Bla的底物，而JDB/NA-1-157是，尽管催化效率较低。这一点得到了如下观察结果的支持：添加阿维巴坦并未增强与JDB/NA-1-157的协同作用。JDB/NA-1-157强大的细菌杀伤作用归因于其对PBP-B、PBP-脂质、PonA2、D，D-羧肽酶和LDT1-2的高结合亲和力。这些发现突出了新型C5α修饰的碳青霉烯类药物，特别是JDB/NA-1-157，作为感染有前景的治疗候选药物的潜力。
