Eukaryotic phosphatase inhibitors enhance colistin efficacy in gram-negative bacteria.
Eukaryotic phosphatase inhibitors enhance colistin efficacy in gram-negative bacteria.
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DOI：
10.1111/cbdd.13735
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发表时间：
2020-11
影响因子：
3
通讯作者：
Melander C
中科院分区：
文献类型：
--
作者：
Barker WT;Jania LA;Melander RJ;Koller BH;Melander C
The mounting threat of multi-drug resistant (MDR) bacteria places a tremendous strain on the antimicrobial clinical arsenal, forcing physicians to revert to near-obsolete antibiotics to treat otherwise intractable infections. Antibiotic adjuvant therapy has emerged as a viable alternative to the development of novel antimicrobial agents. This method uses combinations of an existing antibiotic and a non-antimicrobial small molecule, where the combination either breaks drug resistance or further potentiates antibiotic activity. Through a high-content screen of eukaryotic kinase inhibitors, our group previously identified two highly potent adjuvants that synergize with colistin, a cyclic, polycationic antimicrobial peptide that serves as a drug of last-resort for the treatment of MDR Gram-negative bacterial infections. Cell signaling proteins implicated in colistin resistance mechanisms display both kinase and phosphatase activities. Herein, we explore the potential for eukaryotic phosphatase inhibitors to be repurposed as colistin adjuvants. From a panel of 48 unique structures, we discovered that the natural product kuwanon G breaks colistin resistance, while the non-antimicrobial macrolide ascomycin potentiates colistin in polymyxin-susceptible bacteria.
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