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

Liqiang Hu; Huixin Yang; Tao Yu; Fangfang Chen; Runqiu Liu; Shuyuan Xue; Shuangzhan Zhang; Wuyu Mao; Changge Ji; Hao Wang; Hexin Xie

doi:10.1016/j.ejmech.2022.114174

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. Epub 2022 Feb 4.

Authors

Liqiang Hu¹, Huixin Yang², Tao Yu¹, Fangfang Chen¹, Runqiu Liu¹, Shuyuan Xue¹, Shuangzhan Zhang¹, Wuyu Mao¹, Changge Ji³, Hao Wang⁴, Hexin Xie⁵

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: chicago.ji@gmail.com.
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: xiehexin@ecust.edu.cn.

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.

MeSH terms

Anti-Bacterial Agents* / chemistry
Anti-Bacterial Agents* / pharmacology
Bacteria / drug effects
Cephalosporins* / chemistry
Cephalosporins* / pharmacology
beta-Lactamase Inhibitors* / chemistry
beta-Lactamase Inhibitors* / pharmacology
beta-Lactamases / chemistry

Substances

Anti-Bacterial Agents
Cephalosporins
beta-Lactamase Inhibitors
beta-Lactamases
beta-lactamase NDM-1