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.