biostudies-literatureDutta SNational Institute of Allergy and Infectious DiseasesUniversity of Colorado BoulderNIAID NIH HHSNational Institutes of Health128878https://www.ebi.ac.uk/biostudies/studies/S-EPMC10101151biostudies-literatureUnknown72Multidrug-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.Bioorganic & medicinal chemistry lettersStructure-activity relationship studies of [1,2,5]oxadiazolo[3,4-b]pyrazine-containing polymyxin-selective resistance-modifying agents.PMC10101151R33AI121581R33 AI121581Dutta SLiu NGao YBeck LWang XfalseStructure-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.2022-01-01T00:00:00Z2022 Sep2025-04-19T23:48:01.813Z2025-04-19T23:48:01.813ZS-EPMC101011513578803410.1016/j.bmcl.2022.128878