Structure-activity relationship studies of [1,2,5]oxadiazolo[3,4-b] pyrazine-containing polymyxin-selective resistance-modifying agents

Multidrug-resistant (MDR) Gram-negative bacteria are an urgent and rapidly spreading threat to human health with limited treatment options. Previously, we discovered a novel [1,2,5]oxadiazolo[3,4-b]pyrazine-containing compound (1) that selectively re-sensitized a variety of MDR Gram-negative bacteria to colistin, one of the last-resort antibiotic. Herein, we report the structure-activity relationship studies of compound 1 that led to the discovery of several more potent and/or less toxic resistance-modifying agents (RMAs). Further evaluation of these RMAs showed that they were effective in a wide range of MDR bacteria. These results demonstrated these compounds as a novel class of RMAs and may be further developed as therapeutic agents.

Automated summary

Multidrug-resistant Gram-negative bacteria pose an urgent and rapidly spreading threat to human health. This study discovered a compound that can potentially re-sensitize these bacteria to certain antibiotics. Further investigations led to the identification of more potent and less toxic compounds with potential therapeutic effects against multidrug-resistant bacteria.