2. Academic Validation
  3. Stereochemically altered cephalosporins as potent inhibitors of New Delhi metallo-β-lactamases

Stereochemically altered cephalosporins as potent inhibitors of New Delhi metallo-β-lactamases

  • Eur J Med Chem. 2022 Mar 15;232:114174. doi: 10.1016/j.ejmech.2022.114174.
Liqiang Hu 1,  Huixin Yang 2,  Tao Yu 1,  Fangfang Chen 1,  Runqiu Liu 1,  Shuyuan Xue 1,  Shuangzhan Zhang 1,  Wuyu Mao 1,  Changge Ji 3,  Hao Wang 4,  Hexin Xie 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, Frontiers Science Center for Materiobiology and Dynamic Chemistry, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China.
  • 2 State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, Frontiers Science Center for Materiobiology and Dynamic Chemistry, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China; Clinical Laboratory, Quanzhou Maternity and Children's Hospital, 700 Fengze Street, Quanzhou, Fujian Province, 362000, China.
  • 3 Shanghai Engineering Research Center for Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200062, China. Electronic address: [email protected].
  • 4 Shanghai Engineering Research Center for Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200062, China.
  • 5 State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, Frontiers Science Center for Materiobiology and Dynamic Chemistry, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China. Electronic address: [email protected].
PMID: 35152091 DOI: 10.1016/j.ejmech.2022.114174
Abstract

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.

Keywords

Antibiotic resistance; Inhibitor; New Delhi metallo-β-lactamase; β-lactamase.

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