id7b00106_si_001.pdf (1.07 MB)
Probing the Interaction of Aspergillomarasmine A with Metallo-β-lactamases NDM-1, VIM-2, and IMP‑7
journal contribution
posted 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. CrowderMetallo-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.
