Singh Mangal, Boomgaren Marc, Bakht Perwez, Ihle Patrick, Leiros Hanna-Kirsti S, Bayer Annette, Pathania Ranjana
Department of Biosciences and Bioengineering, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand 247667, India.
Department of Chemistry, UiT the Arctic University of Norway, Tromsø 9037, Norway.
J Med Chem. 2025 Jul 10;68(13):13421-13435. doi: 10.1021/acs.jmedchem.5c00058. Epub 2025 Jun 27.
The global threat posed by multidrug-resistant bacteria, particularly those producing KPC-2 carbapenemases, has compromised the effectiveness of carbapenems, the last-resort antibiotics. To address this, we utilized a bioisosteric replacement approach to synthesize phenylboronic acid (PBA) derivatives targeting KPC-2. The enzyme kinetics study revealed that electron-withdrawing substituents enhanced the residence time of lead compounds, enhancing KPC-2 inhibition. Lead molecule , in synergy with Meropenem, achieved a 3-log CFU/mL reduction in bacterial count within 3 h in time-kill kinetics and exhibited a postantibiotic effect of 71 ± 5 min. A nanomolar range inhibition constant (), a second-order inactivation rate constant (/) of ∼10 M s, and a slow off-rate ( ∼ 0.0018 s) were observed. Importantly, the PBA derivatives were nontoxic to human cells and significantly reduced lung bacterial load in a murine pneumonia model. Overall, PBA-based non-β-lactam β-lactamase inhibitors showed promise in restoring carbapenem efficacy against KPC-2-producers.
多重耐药菌，尤其是那些产生KPC-2碳青霉烯酶的细菌所构成的全球威胁，已经损害了碳青霉烯类药物（即最后的抗生素防线）的有效性。为了解决这一问题，我们采用生物电子等排体替代方法来合成靶向KPC-2的苯硼酸（PBA）衍生物。酶动力学研究表明，吸电子取代基延长了先导化合物的停留时间，增强了对KPC-2的抑制作用。先导分子与美罗培南协同作用，在时间杀菌动力学中3小时内使细菌计数降低了3个对数CFU/mL，并表现出71±5分钟的抗生素后效应。观察到纳摩尔范围的抑制常数（）、约10 M s的二级失活速率常数（/）和缓慢的解离速率（约0.0018 s）。重要的是，PBA衍生物对人类细胞无毒，并在小鼠肺炎模型中显著降低了肺部细菌载量。总体而言，基于PBA的非β-内酰胺β-内酰胺酶抑制剂在恢复碳青霉烯类药物对产KPC-2菌株的疗效方面显示出前景。
