Synthesis and biological evaluation of Aspergillomarasmine A derivatives as novel NDM-1 inhibitor to overcome antibiotics resistance

Jian Zhang; Sanshan Wang; Qi Wei; Qianqian Guo; Yingjie Bai; Shaoqiang Yang; Fuhang Song; Lixin Zhang; Xiaoguang Lei

doi:10.1016/j.bmc.2017.07.025

Synthesis and biological evaluation of Aspergillomarasmine A derivatives as novel NDM-1 inhibitor to overcome antibiotics resistance

Bioorg Med Chem. 2017 Oct 1;25(19):5133-5141. doi: 10.1016/j.bmc.2017.07.025. Epub 2017 Jul 14.

Authors

Jian Zhang¹, Sanshan Wang¹, Qi Wei², Qianqian Guo¹, Yingjie Bai¹, Shaoqiang Yang¹, Fuhang Song², Lixin Zhang³, Xiaoguang Lei⁴

Affiliations

¹ Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Department of Chemical Biology, College of Chemistry and Molecular Engineering, Synthetic and Functional Biomolecules Center, and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
² Chinese Academy of Sciences Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
³ East China University of Science and Technology, Shanghai 200237, China.
⁴ Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Department of Chemical Biology, College of Chemistry and Molecular Engineering, Synthetic and Functional Biomolecules Center, and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China. Electronic address: xglei@pku.edu.cn.

PMID: 28784300
DOI: 10.1016/j.bmc.2017.07.025

Abstract

The β-lactam antibiotic resistance of Gram-negative bacteria has shown to be a critical global health problem. One of the primary reasons for the drug resistance is the existence of β-lactamases especially metallo-β-lactamases such as New Delhi metallo-β-lactamase (NDM-1) and Verona Integron-encoded metallo-β-lactamase (VIM-2). The fungal natural product Aspergillomarasmine A (AMA) has proven to be a promising inhibitor of NDM-1 and VIM-2 both in vitro and in vivo. Seven new analogues of AMA were synthesized by utilizing different strategies. The biological evaluation of these analogues was performed to study the structure-activity relationship of AMA both in vitro and in vivo. Remarkably, the lead compound 4 showed synergistic effect in combination with Meropenem to overcome the antibiotic resistance of the Gram-negative bacteria such as K. pneumoniae (BAA-2146) expressing NDM-1.

Keywords: Antibiotic resistance; Antibiotics; Aspergillomarasmine A; Metallo-β-lactamases; NDM-1.

MeSH terms

Aspartic Acid / analogs & derivatives*
Aspartic Acid / chemical synthesis
Aspartic Acid / chemistry
Aspartic Acid / pharmacology
Humans
Klebsiella Infections / drug therapy
Klebsiella Infections / microbiology
Klebsiella pneumoniae / drug effects*
Klebsiella pneumoniae / enzymology*
beta-Lactam Resistance / drug effects
beta-Lactamase Inhibitors / chemical synthesis
beta-Lactamase Inhibitors / chemistry*
beta-Lactamase Inhibitors / pharmacology*
beta-Lactamases / metabolism*

Substances

beta-Lactamase Inhibitors
Aspartic Acid
aspergillomarasmine A
beta-Lactamases
beta-lactamase NDM-1