Aurones and derivatives as promising New Delhi metallo-β-lactamase (NDM-1) inhibitors

Bacterial resistance is undoubtedly one of the main public health concerns especially with the emergence of metallo-beta-lactamases (MBLs) able to hydrolytically inactivate beta-lactam antibiotics. Currently, there are no inhibitors of MBLs in clinical use to rescue antibiotic action and the New Delhi metallo-beta-lactamase-1 (NDM-1) is still considered as one of the most relevant targets for inhibitor development. Following a fragment-based strategy to find new NDM-1 inhibitors, we identified aurone as a promising scaffold. A series of 60 derivatives were then evaluated and two of them were identified as promising inhibitors with K-i values as low as 1.7 and 2.5 mu M. Moreover, these two most active compounds were able to potentiate meropenem in in vitro antimicrobial susceptibility assays. The molecular modelling provided insights about their likely interactions with the active site of NDM-1, thus enabling further improvement in the structure of this new inhibitor family.