Synthesis of Aspergillomarasmine A and Toxin A Hydroxamic Acid Derivatives for Evaluation as Metallo-β-Lactamase Inhibitors

Abstract

Resistance to β-lactam antibiotics in Gram-negative bacteria is identified by the World Health Organization as a major threat to global health. Such resistance is increasingly mediated by serine- and metallo-β-lactamases, that catalyze beta-lactam hydrolysis. While serine-β-lactamase inhibitors are widely used in combination therapies, there is a lack of clinically approved metallo-β-lactamase inhibitors, although several promising candidates have been identified. Among these, the fungal natural product aspergillomarasmine A (AMA) inhibits metallo-β-lactamases including New Delhi metallo-β-lactamase-1 (NDM-1), restoring the activity of meropenem against resistant isolates. Here, we report robust and scalable routes for the synthesis of AMA and toxin A, enabling selective modifications to be made at each carboxylic acid of the AMA scaffold. Seven hydroxamic acid derivatives were synthesized in addition to cyclic derivatives of AMA and toxin A. The inhibition activities (pIC50 values) of the compounds were evaluated against a range of isolated clinically relevant metallo-β-lactamases, including in the presence of different Zn(II) concentrations. Microbiological assays were performed, with AMA, toxin A, and their hydroxamic acid derivatives restoring the activity of meropenem against carbapenem-resistant Escherichia coli, Klebsiella pneumoniae, and Acinetobacter baumannii strains, obtained from clinical and environmental isolates from Tanzania and Malawi, containing NDM-1 or NDM-5. The synthetic procedures and metallo-β-lactamase inhibition results described will promote and enable further optimization of metallo-β-lactamase inhibitors based on the AMA scaffold.