Extended structure-activity relationship studies of the [1,2,5]oxadiazolo[3,4-b]pyrazine-containing colistin adjuvants

[Display omitted] •Discovered two novel antibiotic adjuvants that re-sensitize multidrug-resistant Gram-negative bacteria to colistin.•Compounds demonstrated broad antibacterial spectrum activity against a variety of clinically relevant pathogens.•Compounds showed high selectivity against resistant bacteria, but not human cells. Antimicrobial resistance (AMR) is a formidable global health challenge. Multidrug-resistant (MDR) Gram-negative bacterial infections are of primary concern due to diminishing treatment options and high morbidity and mortality. Colistin, a polymyxin family antibiotic, is a last-resort treatment for MDR Gram-negative infections, but its wider use has resulted in escalating resistance. In 2022, using a screening approach, we discovered that a [1,2,5]oxadiazolo[3,4-b]pyrazine (ODP)-containing compound selectively re-sensitized various MDR Gram-negative bacteria to colistin. Initial structure–activity relationship (SAR) studies confirmed that bisanilino ODP compounds are colistin adjuvants with low mammalian toxicity. Herein, we report our extended SAR studies on a wide range of ODP analogs bearing alkyl- or arylalkylamines. Specifically, we discovered two new compounds, 5q and 8g, with potent colistin-potentiating activity and low mammalian toxicity in a wide range of clinically relevant pathogens.