Ten years with NDM-1 metallo β-lactamase: from structural insights to inhibitor design

The worldwide emergence of metallo β-lactamase NDM-1 as carbapenemase able to hydrolyze near all available β-lactam antibiotics has characterized the last decade, endangering efficacious antibacterial treatments. No inhibitors for NDM-1 are available in therapy, nor promising compounds are in the pipeline for future NDM-1 inhibitors. We report the studies dedicated to the design and development of effective NDM-1 inhibitors. The discussion for each agent moves from the employed design strategy to the ability of the identified inhibitor to synergize β-lactam antibiotics. A structural analysis of NDM-1 mechanism of action based on selected X-ray complexes is also reported: the intrinsic flexibility of the binding site and the comparison between penicillins/cephalosporins and carbapenems mechanisms of hydrolysis are evaluated. Despite the valuable progresses in terms of structural and mechanistic information, the design of a potent NDM-1 inhibitor to be introduced in therapy remains challenging. Certainly, only the deep knowledge of NDM-1 architecture and of the variable mechanism of action that NDM-1 employs against different classes of substrates could orient a successful drug discovery campaign.