Revisiting aminocoumarins for the treatment of melioidosis

•Aminocoumarins can be used to treat acute pulmonary melioidosis in a murine model.•Formulation with l-tyrosine or dl-tryptophan enhances the bioactivity of aminocoumarins.•Utility of Galleria mellonella larvae for in vivo drug efficacy screening. Burkholderia pseudomallei causes melioidosis, a pote...

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Bibliographic Details
Published in:International journal of antimicrobial agents 2020-07, Vol.56 (1), p.106002, Article 106002
Main Authors: Willcocks, S.J., Cia, F., Francisco, A.F., Wren, B.W.
Format: Article
Language:English
Subjects:
Aminocoumarin
Aminocoumarins - pharmacokinetics
Aminocoumarins - therapeutic use
Animals
Burkholderia pseudomallei
Burkholderia pseudomallei - drug effects
Burkholderia pseudomallei - genetics
Clorobiocin
Coumermycin
Disease Models, Animal
Drug Resistance, Multiple, Bacterial - genetics
Drug Therapy, Combination
Female
Melioidosis
Melioidosis - drug therapy
Mice
Mice, Inbred BALB C
Moths - microbiology
Novobiocin
Novobiocin - analogs & derivatives
Novobiocin - pharmacokinetics
Novobiocin - therapeutic use
Tryptophan - therapeutic use
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Summary:•Aminocoumarins can be used to treat acute pulmonary melioidosis in a murine model.•Formulation with l-tyrosine or dl-tryptophan enhances the bioactivity of aminocoumarins.•Utility of Galleria mellonella larvae for in vivo drug efficacy screening. Burkholderia pseudomallei causes melioidosis, a potentially lethal disease that can establish both chronic and acute infections 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 study, the efficacies of selected aminocoumarin compounds, DNA gyrase inhibitors that were discovered in the 1950s but are not in clinical use for the treatment of melioidosis were investigated. Clorobiocin and coumermycin were shown to be particularly effective in treating B. pseudomallei infection in vivo. A novel formulation with dl-tryptophan or l-tyrosine was shown to further enhance aminocoumarin potency in vivo. It was demonstrated that coumermycin has superior pharmacokinetic properties compared with novobiocin, and the coumermycin in l-tyrosine formulation can be used as an effective treatment for acute respiratory melioidosis in a murine model. Repurposing of existing approved antibiotics offers new resources in a challenging era of drug development and antimicrobial resistance.
ISSN:0924-8579
1872-7913
DOI:10.1016/j.ijantimicag.2020.106002