Probing the interaction of Aspergillomarasmine A (AMA) with metallo-β-lactamases NDM-1, VIM-2, and IMP-7

Bergstrom, A.; Katko, A.; Adkins, Z.B.; Hill, J.E.; Cheng, Z.; Burnett, M.L.; ... ; Crowder, M.W. (2017)

Article / Letter to editor

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.

• All authors: Bergstrom, A.; Katko, A.; Adkins, Z.B.; Hill, J.E.; Cheng, Z.; Burnett, M.L.; Yang, H.; Aitha, M.; Mehaffey, M.R.; Brodbelt, J.S.; Tehrani, K.H.M.E.; Martin, N.I.; Bonomo, R.A.; Page, R.C.; Tierney, D.L.; Fast, W.; Wright, G.D.; Crowder, M.W.
• Date: 2017-11-01
• Journal: ACS Infectious Diseases
• Volume: 4
• Issue: 2
• Pages: 135 - 145
• DOI: doi:10.1021/acsinfecdis.7b00106