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- Title
Pentacyclic nitrofurans that rapidly kill nifurtimox-resistant trypanosomes.
- Authors
Bruhn, David F.; Wyllie, Susan; Rodríguez-Cortés, Adaris; Carrillo, Angela K.; Rakesh; Kiplin Guy, R.; Fairlamb, Alan H.; Lee, Richard E.; Guy, R Kiplin
- Abstract
<bold>Objectives: </bold>In response to reports of Trypanosoma brucei resistance to the nitroaromatic drug nifurtimox, we evaluated the potential of antituberculosis nitrofuran isoxazolines as inhibitors of trypanosome growth.<bold>Methods: </bold>The susceptibility of T. brucei brucei was assessed in vitro. The lowest effective concentration to inhibit growth (EC90) against drug-susceptible and -resistant parasites, time-kill kinetics, reversibility of inhibition and propensity for P-glycoprotein-mediated exclusion from the blood-brain barrier were determined.<bold>Results: </bold>Nitrofuran isoxazolines were potent inhibitors of T. brucei brucei proliferation at nanomolar concentrations, with pentacyclic nitrofurans being 100-fold more potent than nifurtimox. Activity was sustained against nifurtimox-resistant parasites, suggesting the possibility of a unique mechanism of activation and potential for use in the treatment of drug-resistant infections. Exposure of parasites to the maximum concentrations of Compound 15 achieved in vivo with oral dosing yielded >2 logs of irreversible killing in <4 h, indicating rapid trypanocidal activity.<bold>Conclusions: </bold>Pentacyclic nitrofuran isoxazolines warrant further development for the treatment of drug-susceptible and nifurtimox-resistant trypanosome infections.
- Subjects
NITROFURANS; TRYPANOSOMA brucei; GLYCOPROTEINS; DRUG resistance in bacteria; BACTERIAL diseases; ANIMAL experimentation; CELL lines; COMPARATIVE studies; DRUG resistance; DYNAMICS; RESEARCH methodology; MEDICAL cooperation; MICROBIAL sensitivity tests; PROTOZOA; RESEARCH; EVALUATION research; ANTIPROTOZOAL agents; PHARMACODYNAMICS
- Publication
Journal of Antimicrobial Chemotherapy (JAC), 2016, Vol 71, Issue 4, p956
- ISSN
0305-7453
- Publication type
journal article
- DOI
10.1093/jac/dkv417