Since their discovery in 1928 by Alexander Fleming, ß-lactam drugs have been the most successful and commonly prescribed class of antibiotics. Unfortunately, the widespread use of this powerful drug class has created a natural selection pressure for bacteria to adapt and develop resistance mechanisms to these therapeutics; most notably the emergence of ß-lactamase enzymes. ß-lactamases confer bacterial resistance through hydrolysis of the ß-lactam bond that is crucial for the activity of these drugs. New Delhi Metallo-ß-lactamase (NDM-1) is a particularly worrisome metallo-ß-lactamase that utilizes two active site Zn2+ ions to achieve this hydrolytic activity. NDM-1 has been shown to be capable of hydrolyzing all clinically relevant ß-lactams, including the carbapenems – which are considered a last resort drug against resistant infections. Furthermore, NDM-1 is easily communicable between bacteria populations as it is encoded in blaNDM-1, a plasmid capable of horizontal transfer, and has already been detected in multiple strains of enterobacteriaceae. Indeed, since its discovery in India in 2008, NDM-1 has rapidly spread among the general population worldwide and has not been limited to hospital-acquired infections. In addition to this ease of transmission, there are currently no clinically approved drugs available against NDM-1, implicating that NDM-1 has a strong potential to lead to untreatable “superbug” type infections. The ultimate goal of this research is to develop potent inhibitors of NDM-1 to restore ß-lactam activity against resistant bacteria. In order to meet this goal, we have synthesized and screened metal binding pharmacophore (MBP) libraries against NDM-1 to identify MBP fragments that selectively bind to the dinuclear Zn2+ NDM-1 active site. This screen has revealed thiohydroxypyridinone-based compounds, 3-carboxy-1,2-HOPTO and 2-hydroxyisoquinoline-1-thione, as novel scaffolds for the development of NDM-1 inhibitors. The use of a fragment growth strategy to derivatize these compounds has resulted in the discovery of a new, thiohydroxypyridinone-based NDM-1 inhibitor with a potent IC50 of 240 ± 10 nM.

Thiohydroxypyridinones as a scaffold for the development of potent New Delhi metallo-ß-lactamase-1 inhibitors

254th National Meeting (2017)

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