A comprehensive analysis was done to evaluate the potential use of anti-parasitic macrocyclic lactones (including avermectins and milbemycins) for Buruli ulcer (BU) therapy. A panel containing nearly all macrocyclic lactones used in human or in veterinary medicine was analyzed for activity in vitro against clinical isolates of Mycobacterium ulcerans. Milbemycin oxime and selamectin were the most active drugs against M. ulcerans with MIC values from 2 to 8 μg/mL and 2 to 4 μg/mL, respectively. In contrast, ivermectin and moxidectin, which are both in clinical use, showed no significant activity (MIC> 32 μg/mL). Time-kill kinetic assays showed bactericidal activity of selamectin and in vitro pharmacodynamic studies demonstrated exposure-dependent activity. These data together with analyses of published pharmacokinetic information strongly suggest that selamectin is the most promising macrocyclic lactone for BU treatment.
BU can be cured in most cases with the standard treatment, a combination of rifampicin and the injectable antibiotic streptomycin. However, new optimized treatment regimens are needed, especially to prepare for an eventual development of resistance to rifampicin, the most efficacious drug for BU therapy. Since traditional antibacterial drug discovery is not a practical option for BU, using approved drugs for alternative clinical indications would be a more economical and faster way to implement new anti-BU therapies. We reported previously that anti-parasitic avermectins are active against Mycobacterium tuberculosis. Here we show that some are also active in vitro against other mycobacterial species, including M. marinum and M. ulcerans.
In this study, we undertook a comprehensive approach to evaluate additional macrocyclic lactones including compounds used in veterinary medicine. Based on our in vitro measurements of their activities and a literature review of their pharmacokinetic properties, we present strong arguments that selamectin is the avermectin with the highest potential for being repurposed for BU treatment.
BT - PLoS neglected tropical diseases C1 -http://www.ncbi.nlm.nih.gov/pubmed/26270480?dopt=Abstract
DO - 10.1371/journal.pntd.0003996 IS - 8 J2 - PLoS Negl Trop Dis LA - eng N2 -A comprehensive analysis was done to evaluate the potential use of anti-parasitic macrocyclic lactones (including avermectins and milbemycins) for Buruli ulcer (BU) therapy. A panel containing nearly all macrocyclic lactones used in human or in veterinary medicine was analyzed for activity in vitro against clinical isolates of Mycobacterium ulcerans. Milbemycin oxime and selamectin were the most active drugs against M. ulcerans with MIC values from 2 to 8 μg/mL and 2 to 4 μg/mL, respectively. In contrast, ivermectin and moxidectin, which are both in clinical use, showed no significant activity (MIC> 32 μg/mL). Time-kill kinetic assays showed bactericidal activity of selamectin and in vitro pharmacodynamic studies demonstrated exposure-dependent activity. These data together with analyses of published pharmacokinetic information strongly suggest that selamectin is the most promising macrocyclic lactone for BU treatment.
BU can be cured in most cases with the standard treatment, a combination of rifampicin and the injectable antibiotic streptomycin. However, new optimized treatment regimens are needed, especially to prepare for an eventual development of resistance to rifampicin, the most efficacious drug for BU therapy. Since traditional antibacterial drug discovery is not a practical option for BU, using approved drugs for alternative clinical indications would be a more economical and faster way to implement new anti-BU therapies. We reported previously that anti-parasitic avermectins are active against Mycobacterium tuberculosis. Here we show that some are also active in vitro against other mycobacterial species, including M. marinum and M. ulcerans.
In this study, we undertook a comprehensive approach to evaluate additional macrocyclic lactones including compounds used in veterinary medicine. Based on our in vitro measurements of their activities and a literature review of their pharmacokinetic properties, we present strong arguments that selamectin is the avermectin with the highest potential for being repurposed for BU treatment.
PY - 2015 EP - e0003996 T2 - PLoS neglected tropical diseases TI - Selamectin is the avermectin with the best potential for Buruli ulcer treatment. UR - http://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0003996 VL - 9 SN - 1935-2735 ER -