New auranofin analogs with antibacterial properties against Burkholderia clinical isolates

Bacteria of the genus Burkholderia includes pathogenic Burkholderia mallei, Burkholderia pseudomallei and the Burkholderia cepacia complex (Bcc). These Gram-negative pathogens have intrinsic drug resistance, which makes treatment of infections difficult. Bcc affects individuals with cystic fibrosis (CF) and the species B. cenocepacia is associated with one of the worst clinical outcomes. Following the repurposing of auranofin as an antibacterial against Gram-positive bacteria, we previously synthetized auranofin analogs with activity against Gram-negatives. In this work, we show two auranofin analogs, MS-40 and MS-40S have antibiotic activity against Burkholderia clinical isolates. The compounds are bactericidal against B. cenocepacia and kill stationary-phase cells and persisters without selecting for spontaneous resistance. Caenorhabditis elegans and Galleria mellonella tolerated high concentrations of MS-40 and MS-40S, demonstrating these compounds are not toxic in these models organisms. In summary, we show that MS-40 and MS-40S have the potential to be effective therapeutic options to treat Burkholderia infections.