LAUSR

Antibiotic resistance caused by β-lactamases, particularly metallo-β-lactamases, has been a major threat to public health globally. New Delhi metallo-β-lactamase-1 (NDM-1) represents one of the most important metallo-β-lactamases; the production of NDM-1 in bacterial pathogen significantly reduces the efficacy of β-lactam antibiotics, including life-saving carbapenems. Herein, we have demonstrated stereochemically altered cephalosporins as potent inhibitors against NDM-1, as well as mutants of NDM. The structure and activity relationship (SAR) study on over twenty cephalosporin analogues discloses the stereochemistry and the substituents on 7-position and 3'-position of cephalosporin are critical to suppress the activity of NDM-1 and the optimal compound 1u exhibited an IC50 of 0.13 μM. Furthermore, a crystal complex of NDM-1 and 1u has been obtained, suggesting this cephalosporin derivative inhibits enzyme activity by the formation of a relatively stable hydrolytic product-NDM-1 intermediate. The discovery in this study may pave the way to turn cephalosporin, a natural substrate of β-lactamase, into an effective NDM-1 inhibitor to combat antibiotic resistance.