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

doi:10.1093/jac/dkv417

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)

Biological Chemistry and Drug Discovery

Research output: Contribution to journal › Article › peer-review

5 Citations (Scopus)

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 language	English
Article number	dkv417
Pages (from-to)	956-963
Number of pages	8
Journal	Journal of Antimicrobial Chemotherapy
Volume	71
Issue number	4
Early online date	18 Dec 2015
DOIs	https://doi.org/10.1093/jac/dkv417
Publication status	Published - Apr 2016

Keywords

nifurtimox
nitrofurans
parasites
trypanosoma
kinetics

ASJC Scopus subject areas

Pharmacology
Pharmacology (medical)
Infectious Diseases

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1093/jac/dkv417

Cite this

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title = "Pentacyclic nitrofurans that rapidly kill nifurtimox-resistant trypanosomes",

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 ",

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author = "Bruhn, {David F.} and Susan Wyllie and Adaris Rodr{\'i}guez-Cort{\'e}s and Carrillo, {Angela K.} and Rakesh and Guy, {R. Kiplin} and Fairlamb, {Alan H.} and Lee, {Richard E.}",

note = "This study was supported by the National Institutes of Health grants R01AI062145 and the American Lebanese Syrian Associated Charities (ALSAC), St Jude Children's Research Hospital. A. H. F. and S. W. are funded by the Wellcome Trust (079838).",

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doi = "10.1093/jac/dkv417",

language = "English",

volume = "71",

pages = "956--963",

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AU - Bruhn, David F.

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.

N1 - This study was supported by the National Institutes of Health grants R01AI062145 and the American Lebanese Syrian Associated Charities (ALSAC), St Jude Children's Research Hospital. A. H. F. and S. W. are funded by the Wellcome Trust (079838).

PY - 2016/4

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AB - 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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Pentacyclic nitrofurans that rapidly kill nifurtimox-resistant trypanosomes

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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Aref#d: 18185. Characterization and validation of drug targets in the Kinetoplastida (Principal Research Fellowship/Programme Grant)

Cite this

Pentacyclic nitrofurans that rapidly kill nifurtimox-resistant trypanosomes

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Projects

Aref#d: 18185. Characterization and validation of drug targets in the Kinetoplastida (Principal Research Fellowship/Programme Grant)

Cite this