Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, Florida, USA
Servicio de Microbiologia and Unidad de Investigacion, Hospital Universitario Son Espases, Instituto de Investigacion Sanitaria Illes Balears (IdISBa), Palma de Mallorca, Spain.
Antimicrob Agents Chemother. 2019 Apr 25;63(5). doi: 10.1128/AAC.00128-19. Print 2019 May.
Zidebactam and WCK 5153 are novel bicyclo-acyl hydrazide (BCH) agents that have previously been shown to act as β-lactam enhancer (BLE) antibiotics in and The objectives of this work were to identify the molecular targets of these BCHs in and to investigate their potential BLE activity for cefepime and aztreonam against metallo-β-lactamase (MBL)-producing strains and Penicillin binding protein (PBP) binding profiles were determined by Bocillin FL assay, and 50% inhibitory concentrations (ICs) were determined using ImageQuant TL software. MICs and kill kinetics for zidebactam, WCK 5153, and cefepime or aztreonam, alone and in combination, were determined against clinical isolates producing MBLs VIM-1 or NDM-1 (plus ESBLs and class C β-lactamases) to assess the enhancer effect of BCH compounds in conjunction with β-lactams. Additionally, murine systemic and thigh infection studies were conducted to evaluate BLE effects Zidebactam and WCK 5153 showed specific, high PBP2 affinity in The MICs of BLEs were >64 μg/ml for all MBL-producing strains. Time-kill studies showed that a combination of these BLEs with either cefepime or aztreonam provided 1 to >3 log kill against MBL-producing strains. Furthermore, the bactericidal synergy observed for these BLE-β-lactam combinations translated well into efficacy even in the absence of MBL inhibition by BLEs, a characteristic feature of the β-lactam enhancer mechanism of action. Zidebactam and WCK 5153 are potent PBP2 inhibitors and display and BLE effects against multidrug-resistant (MDR) clinical isolates producing MBLs.
齐他培南和 WCK 5153 是新型双环酰肼（BCH）类化合物，先前已被证实可作为β-内酰胺增强剂（BLE）抗生素，分别在 和 中发挥作用。本研究的目的是确定这些 BCH 在 中的分子靶点，并研究它们对产金属β-内酰胺酶（MBL）菌株中头孢吡肟和氨曲南的潜在 BLE 活性。通过 Bocillin FL 检测法确定青霉素结合蛋白（PBP）结合谱，并使用 ImageQuant TL 软件测定 50%抑制浓度（IC）。单独及联合使用齐他培南、WCK 5153、头孢吡肟或氨曲南，针对产 VIM-1 或 NDM-1 MBL（同时产 ESBL 和 C 类β-内酰胺酶）的临床分离株，测定 MIC 和杀菌动力学，以评估 BCH 化合物与β-内酰胺联合使用时的增强作用。此外，还进行了小鼠全身和大腿感染研究，以评估 BLE 效应。齐他培南和 WCK 5153 在 中显示出对 PBP2 的特异性高亲和力。BLE 对所有产 MBL 株的 MIC 均大于 64μg/ml。时间杀伤研究表明，这些 BLE 与头孢吡肟或氨曲南联合使用可对产 MBL 株提供 1 至 >3 对数杀灭。此外，这些 BLE-内酰胺组合的杀菌协同作用在缺乏 BLE 对 MBL 的抑制作用时也能很好地转化为体内疗效，这是 BLE 作用机制的一个特征。齐他培南和 WCK 5153 是强效的 PBP2 抑制剂，对产 MBL 的多药耐药（MDR）临床分离株具有 和 BLE 作用。
