Three-Dimensional Structure and Optimization of the Metallo-β-Lactamase Inhibitor Aspergillomarasmine A

The aminopolycarboxylic
acid aspergillomarasmine A (AMA) is a natural
Zn2+ metallophore and inhibitor of metallo-β-lactamases
(MBLs) which reverses β-lactam resistance. The first crystal
structure of an AMA coordination complex is reported and reveals a
pentadentate ligand with distorted octahedral geometry. We report
the solid-phase synthesis of 23 novel analogs of AMA involving structural
diversification of each subunit (l-Asp, l-APA1,
and l-APA2). Inhibitory activity was evaluated in vitro using
five strains of Escherichia coli producing
globally prevalent MBLs. Further in vitro assessment was performed
with purified recombinant enzymes and intracellular accumulation studies.
Highly constrained structure–activity relationships were demonstrated,
but three analogs revealed favorable characteristics where either
Zn2+ affinity or the binding mode to MBLs were improved.
This study identifies compounds that can further be developed to produce
more potent and broader-spectrum MBL inhibitors with improved pharmacodynamic/pharmacokinetic
properties.