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

Publication date: 1 October 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 19
Author(s): Jian Zhang, Sanshan Wang, Qi Wei, Qianqian Guo, Yingjie Bai, Shaoqiang Yang, Fuhang Song, Lixin Zhang, Xiaoguang Lei
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.

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