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

Area of Science:

• Biochemistry
• Microbiology
• Drug Discovery

Background:

• Metallo-β-lactamases (MBLs) are a significant threat to the effectiveness of β-lactam antibiotics.
• Aspergillomarasmine A (AMA) is a known inhibitor of MBLs, but its precise mechanism of action requires further elucidation.

Purpose of the Study:

• To characterize the mode of inhibition of MBLs by aspergillomarasmine A.
• To investigate the interaction between AMA and the active site metal ions of clinically relevant MBLs.

Main Methods:

• Equilibrium dialysis and metal analysis were employed to study the removal of Zn(II) from MBLs by AMA.
• Proton nuclear magnetic resonance (¹H NMR) spectroscopy was used to analyze the removal of Co(II) from Co(II)-substituted MBLs by AMA.

Main Results:

• AMA effectively removes Zn(II) from MBLs (NDM-1, VIM-2, IMP-7) at micromolar concentrations.
• AMA also removes Co(II) from Co(II)-substituted MBLs at millimolar concentrations, with a 2:2 stoichiometry.
• The findings indicate that AMA inhibits MBLs by chelating the active site metal ions crucial for antibiotic hydrolysis.

Conclusions:

• Aspergillomarasmine A inhibits metallo-β-lactamases by sequestering essential active site metal ions.
• This mechanism highlights AMA's potential as a therapeutic agent against infections caused by MBL-producing bacteria.
• Understanding AMA's inhibitory action provides insights for developing novel strategies to combat antibiotic resistance.