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Probing the Interaction of Aspergillomarasmine A with Metallo-β-lactamases NDM-1, VIM-2, and IMP‑7
journal contributionposted on 2017-11-01, 00:00 authored by Alexander Bergstrom, Andrew Katko, Zach Adkins, Jessica Hill, Zishuo Cheng, Mia Burnett, Hao Yang, Mahesh Aitha, M. Rachel Mehaffey, Jennifer S. Brodbelt, Kamaleddin H. M. E. Tehrani, Nathaniel I. Martin, Robert A. Bonomo, Richard C. Page, David L. Tierney, Walter Fast, Gerard D. Wright, Michael W. Crowder
Metallo-β-lactamases (MBLs) are a growing threat to the continued efficacy of β-lactam antibiotics. Recently, aspergillomarasmine A (AMA) was identified as an MBL inhibitor, but the mode of inhibition was not fully characterized. Equilibrium dialysis and metal analysis studies revealed that 2 equiv of AMA effectively removes 1 equiv of Zn(II) from MBLs NDM-1, VIM-2, and IMP-7 when the MBL is at micromolar concentrations. Conversely, 1H NMR studies revealed that 2 equiv of AMA remove 2 equiv of Co(II) from Co(II)-substituted NDM-1, VIM-2, and IMP-7 when the MBL/AMA are at millimolar concentrations. Our findings reveal that AMA inhibits the MBLs by removal of the active site metal ions required for β-lactam hydrolysis among the most clinically significant MBLs.