H2depda: An acyclic adjuvant potentiates meropenem activity in vitro against metallo-β-lactamase-producing enterobacterales

Xiu-Fang Shi; Ming-Ming Wang; Shu-Chao Huang; Jiang-Xue Han; Wen-Chao Chu; Chunling Xiao; En Zhang; Shangshang Qin

doi:10.1016/j.ejmech.2019.01.083

H₂depda: An acyclic adjuvant potentiates meropenem activity in vitro against metallo-β-lactamase-producing enterobacterales

Eur J Med Chem. 2019 Apr 1:167:367-376. doi: 10.1016/j.ejmech.2019.01.083. Epub 2019 Feb 1.

Authors

Xiu-Fang Shi¹, Ming-Ming Wang¹, Shu-Chao Huang², Jiang-Xue Han², Wen-Chao Chu¹, Chunling Xiao², En Zhang³, Shangshang Qin⁴

Affiliations

¹ School of Pharmaceutical Sciences, Institute of Drug Discovery and Development, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Zhengzhou University, Zhengzhou, 450001, PR China.
² Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China.
³ School of Pharmaceutical Sciences, Institute of Drug Discovery and Development, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Zhengzhou University, Zhengzhou, 450001, PR China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Zhengzhou, 450001, PR China. Electronic address: zhangen@zzu.edu.cn.
⁴ School of Pharmaceutical Sciences, Institute of Drug Discovery and Development, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Zhengzhou University, Zhengzhou, 450001, PR China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Zhengzhou, 450001, PR China. Electronic address: qinshangshang@126.com.

PMID: 30776696
DOI: 10.1016/j.ejmech.2019.01.083

Abstract

Metallo-β-lactamase (MBL)-producing carbapenem-resistant Enterobacterales (CRE) pose an emerging threat to public health worldwide. An effective inhibitor of MBLs is therefore urgently needed for clinical use. In this study, two acyclic pyridine-containing ligands, H₂dedpa and compound 8, were discovered with excellent activities when combined with meropenem (MEM) against MBL (bla_NDM and bla_IMP)-producing clinical isolates, including Escherichia coli, Citrobacter freundii, Proteus mirabilis, Enterobacter cloacae and Klebsiella pneumoniae. In particular, these two compounds improved the activity of MEM against E. coli harboring the bla_NDM-4 gene by nearly 40,960 times. H₂dedpa (IC₅₀ = 0.17 ± 0.04 μM) and compound 8 (IC₅₀ = 0.04 ± 0.02 μM) showed higher inhibitory activity against bla_NDM-1 enzyme than the positive control ethylenediaminetetraacetic acid (EDTA, IC₅₀ = 28.84 ± 0.70 μM). A sterilization kinetics experiment showed that H₂dedpain combined with MEM could kill 99.9% of bacteria within 24 h H₂dedpa and compound 8 are therefore promising MBL inhibitors.

Keywords: Antibiotic resistance; Metallo-β-lactamase inhibitors; New Delhi-metallo-1.

MeSH terms

Drug Resistance, Bacterial / genetics
Drug Synergism
Drug Therapy, Combination
Enterobacter / drug effects*
Enterobacter / enzymology
Enzyme Inhibitors / pharmacology
Escherichia coli / drug effects
Escherichia coli / enzymology
Escherichia coli / genetics
Ethylamines / pharmacology*
Ligands
Meropenem / pharmacology*
Pyridines / chemistry
Pyridines / pharmacology*
beta-Lactamases / drug effects
beta-Lactamases / genetics
beta-Lactamases / isolation & purification

Substances

Enzyme Inhibitors
Ethylamines
Ligands
N,N'-((6-carboxylato)pyridin-2-yl)methyl)-1,2-diaminoethane
Pyridines
beta-Lactamases
Meropenem