Laboratorio de Metaloproteínas, Instituto de Biología Molecular y Celular de Rosario (IBR, CONICET-UNR), Rosario, Argentina.
Research Service, Veterans Affairs Northeast Ohio Healthcare System, Cleveland, Ohio, USA; Departments of Medicine, Pharmacology, Molecular Biology and Microbiology, Biochemistry, and Proteomics and Bioinformatics, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA; Medical Service and GRECC, Veterans Affairs Northeast Ohio Healthcare System, Cleveland, Ohio, USA; U.S. Department of Veterans Affairs, CWRU-Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology (Case VA CARES), Cleveland, Ohio, USA.
J Biol Chem. 2022 Mar;298(3):101665. doi: 10.1016/j.jbc.2022.101665. Epub 2022 Feb 1.
Understanding the evolution of metallo-β-lactamases (MBLs) is fundamental to deciphering the mechanistic basis of resistance to carbapenems in pathogenic and opportunistic bacteria. Presently, these MBL-producing pathogens are linked to high rates of morbidity and mortality worldwide. However, the study of the biochemical and biophysical features of MBLs in vitro provides an incomplete picture of their evolutionary potential, since this limited and artificial environment disregards the physiological context where evolution and selection take place. Herein, we describe recent efforts aimed to address the evolutionary traits acquired by different clinical variants of MBLs in conditions mimicking their native environment (the bacterial periplasm) and considering whether they are soluble or membrane-bound proteins. This includes addressing the metal content of MBLs within the cell under zinc starvation conditions and the context provided by different bacterial hosts that result in particular resistance phenotypes. Our analysis highlights recent progress bridging the gap between in vitro and in-cell studies.
了解金属β-内酰胺酶（MBLs）的进化对于揭示致病和机会性细菌对碳青霉烯类药物耐药的机制基础至关重要。目前，这些产 MBL 的病原体与全球高发病率和死亡率有关。然而，在体外研究 MBL 的生化和生物物理特性提供了其进化潜力的不完整图景，因为这种有限和人为的环境忽略了发生进化和选择的生理环境。在此，我们描述了最近的努力，旨在解决不同临床变异型 MBL 在模拟其天然环境（细菌周质）的条件下获得的进化特征，并考虑它们是可溶性还是膜结合蛋白。这包括在缺锌条件下解决细胞内 MBL 的金属含量以及不同细菌宿主提供的导致特定耐药表型的环境。我们的分析强调了在细胞外和细胞内研究之间架起桥梁的最新进展。
