首页|Stereochemically altered cephalosporins as potent inhibitors of New Delhi metallo-beta-lactamases
Stereochemically altered cephalosporins as potent inhibitors of New Delhi metallo-beta-lactamases
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NSTL
Antibiotic resistance caused by beta-lactamases, particularly metallo-beta-lactamases, has been a major threat to public health globally. New Delhi metallo-beta-lactamase-1 (NDM-1) represents one of the most important metallo-beta-lactamases; the production of NDM-1 in bacterial pathogen significantly reduces the efficacy of beta-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 30-position of cephalosporin are critical to suppress the activity of NDM-1 and the optimal compound 1u exhibited an IC50 of 0.13 mM. 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 beta-lactamase, into an effective NDM-1 inhibitor to combat antibiotic resistance. (c) 2022 Elsevier Masson SAS. All rights reserved.
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