Probing the Interaction of Aspergillomarasmine A with Metallo-beta-lactamases NDM-1, VIM-2, and IMP-7

Metallo-beta-lactamases (MBLs) are a growing threat to the continued efficacy of beta-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, H-1 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 beta-lactam hydrolysis among the most clinically significant MBLs.