Total Synthesis and Structural Reassignment of Aspergillomarasmine A

Abstract

The increase and spread of Gram-negative bacteria that resistant are to almost all currently available β-lactam antibiotics is a major global health problem. The primary cause for drug resistance is the acquisition of metallo-β-lactamases such as metallo-β-lactamase-1 (NDM-1). The fungal natural product aspergillomarasmine A (AMA), a fungal natural product, is an inhibitor of NDM-1 and has shown promising in vivo therapeutic potential in a mouse model infected with NDM-1-expressing Gram-negative bacteria. The first total synthesis and stereochemical configuration reassignment of aspergillomarasmine A is reported. The synthesis highlights a flexible route and an effective strategy to achieve the required oxidation state at a late stage. This modular route is amenable to the efficient preparation of analogues for the development of metallo-β-lactamase inhibitors to potentiate β-lactam antibiotics.

Keywords: antibiotics; aspergillomarasmine A; metallo-β-lactamase; structural reassignment; total synthesis.