Synthesis and biological evaluation of Aspergillomarasmine A derivatives as novel NDM-1 inhibitor to overcome antibiotics resistance.
Zhang, J.; Wang, S.; Wei, Q.; Guo, Q.; Bai, Y.; Yang, S.; Song, F.; Zhang, L.; Lei, X
Bioorg. Med. Chem. 2017, 25, 5133-5141.
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.
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:Arabidopsis; bioassay-guided fractionation; plasma membrane H+-ATPase; unsaturated fatty acids