Revisiting Aminocoumarins for the Treatment of Melioidosis.

Abstract Burkholderia pseudomallei causes melioidosis, a potentially lethal disease that can establish both chronic and acute infection in humans. It is inherently recalcitrant to many antibiotics, there is a paucity of effective treatment options, and there is no vaccine. In the present work, we investigate the efficacy of selected aminocoumarin compounds, DNA gyrase inhibitors that were discovered in the 1950’s but are not in clinical use for the treatment of melioidosis. We show that chlorobiocin and coumermycin are particularly effective in treating B. pseudomallei infection in vivo, and report that a novel formulation with DL-tryptophan or L- tyrosine can further enhance aminocoumarin potency in vivo. We demonstrate that coumermycin has superior pharmacokinetic properties compared with novobiocin and report that coumermycin in L-tyrosine formulation can be used as an effective treatment for acute respiratory melioidosis in the murine model. Repurposing existing approved antibiotics offers new resources in a challenging era of drug development and antimicrobial resistance.