[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]
Synergistic effect of colistin combined with PFK-158 against colistin-resistant Enterobacteriaceae
Youwen Zhang, Xiukun Wang, Xue Li, Limin Dong, Xinxin Hu, Tongying Nie, Yun Lu, Xi Lu, Jing Pang, Guoqing Li, Xinyi Yang, Congran Li, Xuefu You
As increasing numbers of colistin-resistant bacteria emerge, new therapies are urgently needed to treat infections caused by these pathogens. The discovery of new combination therapies is one important way to solve such problems. Herein, we report that the antitumor drug PFK-158 and its analogs PFK-015 and 3PO can exert synergistic effects with colistin against colistin-resistant Enterobacteriaceae, including mcr-1 positive or high-level colistin resistant (HLCR) isolates, as shown by a checkerboard assay. The results of a time-killing assay revealed that colistin combined with PFK-158 continuously eliminated colistin-resistant Escherichia coli 13-43, Klebsiella pneumoniae H04 and Enterobacter cloacae D01 in 24 h. Images from scanning electron microscopy (SEM) 5 h post-inoculation confirmed the killing effect of the combination. Finally, the in vivo treatment showed that PFK-158 had a better synergistic effect than its analogs. Compared to the corresponding rates after colistin monotherapy, the survival rates of systemically infected mice were significantly increased 30% or 60% when the mice received an intravenous injection of colistin in combination with 15 mg/kg PFK-158. These results have important implications for repurposing PFK-158 to combat colistin resistance.
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Keywords: Antibiotics; Drugs Resistance; Enterobacteriaceae; MCR1; Colistin.