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AR-13, a Celecoxib Derivative, Directly Kills Francisella In Vitro and Aids Clearance and Mouse Survival In Vivo

Francisella tularensis (F. tularensis) is the causative agent of tularemia and is classified as a Tier 1 select agent. No licensed vaccine is currently available in the United States and treatment of tularemia is confined to few antibiotics. In this study, we demonstrate that AR-13, a derivative of...

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Autores principales: Hoang, Ky V., Adcox, Haley E., Fitch, James R., Gordon, David M., Curry, Heather M., Schlesinger, Larry S., White, Peter, Gunn, John S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5600997/
https://www.ncbi.nlm.nih.gov/pubmed/28955308
http://dx.doi.org/10.3389/fmicb.2017.01695
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author Hoang, Ky V.
Adcox, Haley E.
Fitch, James R.
Gordon, David M.
Curry, Heather M.
Schlesinger, Larry S.
White, Peter
Gunn, John S.
author_facet Hoang, Ky V.
Adcox, Haley E.
Fitch, James R.
Gordon, David M.
Curry, Heather M.
Schlesinger, Larry S.
White, Peter
Gunn, John S.
author_sort Hoang, Ky V.
collection PubMed
description Francisella tularensis (F. tularensis) is the causative agent of tularemia and is classified as a Tier 1 select agent. No licensed vaccine is currently available in the United States and treatment of tularemia is confined to few antibiotics. In this study, we demonstrate that AR-13, a derivative of the cyclooxygenase-2 inhibitor celecoxib, exhibits direct in vitro bactericidal killing activity against Francisella including a type A strain of F. tularensis (SchuS4) and the live vaccine strain (LVS), as well as toward the intracellular proliferation of LVS in macrophages, without causing significant host cell toxicity. Identification of an AR-13-resistant isolate indicates that this compound has an intracellular target(s) and that efflux pumps can mediate AR-13 resistance. In the mouse model of tularemia, AR-13 treatment protected 50% of the mice from lethal LVS infection and prolonged survival time from a lethal dose of F. tularensis SchuS4. Combination of AR-13 with a sub-optimal dose of gentamicin protected 60% of F. tularensis SchuS4-infected mice from death. Taken together, these data support the translational potential of AR-13 as a lead compound for the further development of new anti-Francisella agents.
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spelling pubmed-56009972017-09-27 AR-13, a Celecoxib Derivative, Directly Kills Francisella In Vitro and Aids Clearance and Mouse Survival In Vivo Hoang, Ky V. Adcox, Haley E. Fitch, James R. Gordon, David M. Curry, Heather M. Schlesinger, Larry S. White, Peter Gunn, John S. Front Microbiol Microbiology Francisella tularensis (F. tularensis) is the causative agent of tularemia and is classified as a Tier 1 select agent. No licensed vaccine is currently available in the United States and treatment of tularemia is confined to few antibiotics. In this study, we demonstrate that AR-13, a derivative of the cyclooxygenase-2 inhibitor celecoxib, exhibits direct in vitro bactericidal killing activity against Francisella including a type A strain of F. tularensis (SchuS4) and the live vaccine strain (LVS), as well as toward the intracellular proliferation of LVS in macrophages, without causing significant host cell toxicity. Identification of an AR-13-resistant isolate indicates that this compound has an intracellular target(s) and that efflux pumps can mediate AR-13 resistance. In the mouse model of tularemia, AR-13 treatment protected 50% of the mice from lethal LVS infection and prolonged survival time from a lethal dose of F. tularensis SchuS4. Combination of AR-13 with a sub-optimal dose of gentamicin protected 60% of F. tularensis SchuS4-infected mice from death. Taken together, these data support the translational potential of AR-13 as a lead compound for the further development of new anti-Francisella agents. Frontiers Media S.A. 2017-09-11 /pmc/articles/PMC5600997/ /pubmed/28955308 http://dx.doi.org/10.3389/fmicb.2017.01695 Text en Copyright © 2017 Hoang, Adcox, Fitch, Gordon, Curry, Schlesinger, White and Gunn. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Microbiology
Hoang, Ky V.
Adcox, Haley E.
Fitch, James R.
Gordon, David M.
Curry, Heather M.
Schlesinger, Larry S.
White, Peter
Gunn, John S.
AR-13, a Celecoxib Derivative, Directly Kills Francisella In Vitro and Aids Clearance and Mouse Survival In Vivo
title AR-13, a Celecoxib Derivative, Directly Kills Francisella In Vitro and Aids Clearance and Mouse Survival In Vivo
title_full AR-13, a Celecoxib Derivative, Directly Kills Francisella In Vitro and Aids Clearance and Mouse Survival In Vivo
title_fullStr AR-13, a Celecoxib Derivative, Directly Kills Francisella In Vitro and Aids Clearance and Mouse Survival In Vivo
title_full_unstemmed AR-13, a Celecoxib Derivative, Directly Kills Francisella In Vitro and Aids Clearance and Mouse Survival In Vivo
title_short AR-13, a Celecoxib Derivative, Directly Kills Francisella In Vitro and Aids Clearance and Mouse Survival In Vivo
title_sort ar-13, a celecoxib derivative, directly kills francisella in vitro and aids clearance and mouse survival in vivo
topic Microbiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5600997/
https://www.ncbi.nlm.nih.gov/pubmed/28955308
http://dx.doi.org/10.3389/fmicb.2017.01695
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