Pentacyclic nitrofurans that rapidly kill nifurtimox-resistant trypanosomes

David F. Bruhn, Susan Wyllie, Adaris Rodríguez-Cortés, Angela K. Carrillo, Rakesh, R. Kiplin Guy, Alan H. Fairlamb, Richard E. Lee (Lead / Corresponding author)

Research output: Contribution to journalArticle

Abstract

Objectives: 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. 

Methods: 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. 

Results: 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

Original languageEnglish
Article numberdkv417
Pages (from-to)956-963
Number of pages8
JournalJournal of Antimicrobial Chemotherapy
Volume71
Issue number4
Early online date18 Dec 2015
DOIs
Publication statusPublished - Apr 2016

Fingerprint

Nifurtimox
Nitrofurans
Trypanosoma brucei brucei
Trypanosomiasis
Parasites
Pharmaceutical Preparations
Growth Inhibitors
P-Glycoprotein
Blood-Brain Barrier
Growth
Infection

Keywords

  • nifurtimox
  • nitrofurans
  • parasites
  • trypanosoma
  • kinetics

Cite this

Bruhn, D. F., Wyllie, S., Rodríguez-Cortés, A., Carrillo, A. K., Rakesh, Guy, R. K., ... Lee, R. E. (2016). Pentacyclic nitrofurans that rapidly kill nifurtimox-resistant trypanosomes. Journal of Antimicrobial Chemotherapy, 71(4), 956-963. [dkv417]. https://doi.org/10.1093/jac/dkv417
Bruhn, David F. ; Wyllie, Susan ; Rodríguez-Cortés, Adaris ; Carrillo, Angela K. ; Rakesh ; Guy, R. Kiplin ; Fairlamb, Alan H. ; Lee, Richard E. / Pentacyclic nitrofurans that rapidly kill nifurtimox-resistant trypanosomes. In: Journal of Antimicrobial Chemotherapy. 2016 ; Vol. 71, No. 4. pp. 956-963.
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Bruhn, DF, Wyllie, S, Rodríguez-Cortés, A, Carrillo, AK, Rakesh, Guy, RK, Fairlamb, AH & Lee, RE 2016, 'Pentacyclic nitrofurans that rapidly kill nifurtimox-resistant trypanosomes', Journal of Antimicrobial Chemotherapy, vol. 71, no. 4, dkv417, pp. 956-963. https://doi.org/10.1093/jac/dkv417

Pentacyclic nitrofurans that rapidly kill nifurtimox-resistant trypanosomes. / Bruhn, David F.; Wyllie, Susan; Rodríguez-Cortés, Adaris; Carrillo, Angela K.; Rakesh; Guy, R. Kiplin; Fairlamb, Alan H.; Lee, Richard E. (Lead / Corresponding author).

In: Journal of Antimicrobial Chemotherapy, Vol. 71, No. 4, dkv417, 04.2016, p. 956-963.

Research output: Contribution to journalArticle

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AU - Wyllie, Susan

AU - Rodríguez-Cortés, Adaris

AU - Carrillo, Angela K.

AU - Rakesh,

AU - Guy, R. Kiplin

AU - Fairlamb, Alan H.

AU - Lee, Richard E.

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N2 - Objectives: 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. Methods: 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. Results: 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

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