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Efflux pump-mediated resistance to antifungal compounds can be prevented by conjugation with triphenylphosphonium cation

Antifungal resistance due to upregulation of efflux pumps is prevalent in clinical Candida isolates. Potential efflux pump substrates (PEPSs), which are active against strains deficient in efflux pumps but inactive against wild-type strains, are usually missed in routine antifungal screening. Here w...

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Autores principales: Chang, Wenqiang, Liu, Jun, Zhang, Ming, Shi, Hongzhuo, Zheng, Sha, Jin, Xueyang, Gao, Yanhui, Wang, Shuqi, Ji, Aiguo, Lou, Hongxiang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6269435/
https://www.ncbi.nlm.nih.gov/pubmed/30504815
http://dx.doi.org/10.1038/s41467-018-07633-9
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author Chang, Wenqiang
Liu, Jun
Zhang, Ming
Shi, Hongzhuo
Zheng, Sha
Jin, Xueyang
Gao, Yanhui
Wang, Shuqi
Ji, Aiguo
Lou, Hongxiang
author_facet Chang, Wenqiang
Liu, Jun
Zhang, Ming
Shi, Hongzhuo
Zheng, Sha
Jin, Xueyang
Gao, Yanhui
Wang, Shuqi
Ji, Aiguo
Lou, Hongxiang
author_sort Chang, Wenqiang
collection PubMed
description Antifungal resistance due to upregulation of efflux pumps is prevalent in clinical Candida isolates. Potential efflux pump substrates (PEPSs), which are active against strains deficient in efflux pumps but inactive against wild-type strains, are usually missed in routine antifungal screening. Here we present a method for identification of PEPSs, and show that conjugation with mitochondria-targeting triphenylphosphonium cation (TPP(+)) can enhance or restore the compounds’ antifungal activity. The screening method involves co-culturing a wild-type C. albicans strain and a Cdr efflux pump-deficient strain, labelled with different fluorescent proteins. We identify several PEPSs from a library of natural terpenes, and restore their antifungal activity against wild-type and azole-resistant C. albicans by conjugation with TPP(+). The most active conjugate (IS-2-Pi-TPP) kills C. albicans cells, prevents biofilm formation and eliminates preformed biofilms, without inducing significant resistance. The antifungal activity is accompanied by mitochondrial dysfunction and increased levels of intracellular reactive oxygen species. In addition, IS-2-Pi-TPP is effective against C. albicans in a mouse model of skin infection.
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spelling pubmed-62694352018-12-03 Efflux pump-mediated resistance to antifungal compounds can be prevented by conjugation with triphenylphosphonium cation Chang, Wenqiang Liu, Jun Zhang, Ming Shi, Hongzhuo Zheng, Sha Jin, Xueyang Gao, Yanhui Wang, Shuqi Ji, Aiguo Lou, Hongxiang Nat Commun Article Antifungal resistance due to upregulation of efflux pumps is prevalent in clinical Candida isolates. Potential efflux pump substrates (PEPSs), which are active against strains deficient in efflux pumps but inactive against wild-type strains, are usually missed in routine antifungal screening. Here we present a method for identification of PEPSs, and show that conjugation with mitochondria-targeting triphenylphosphonium cation (TPP(+)) can enhance or restore the compounds’ antifungal activity. The screening method involves co-culturing a wild-type C. albicans strain and a Cdr efflux pump-deficient strain, labelled with different fluorescent proteins. We identify several PEPSs from a library of natural terpenes, and restore their antifungal activity against wild-type and azole-resistant C. albicans by conjugation with TPP(+). The most active conjugate (IS-2-Pi-TPP) kills C. albicans cells, prevents biofilm formation and eliminates preformed biofilms, without inducing significant resistance. The antifungal activity is accompanied by mitochondrial dysfunction and increased levels of intracellular reactive oxygen species. In addition, IS-2-Pi-TPP is effective against C. albicans in a mouse model of skin infection. Nature Publishing Group UK 2018-11-30 /pmc/articles/PMC6269435/ /pubmed/30504815 http://dx.doi.org/10.1038/s41467-018-07633-9 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Chang, Wenqiang
Liu, Jun
Zhang, Ming
Shi, Hongzhuo
Zheng, Sha
Jin, Xueyang
Gao, Yanhui
Wang, Shuqi
Ji, Aiguo
Lou, Hongxiang
Efflux pump-mediated resistance to antifungal compounds can be prevented by conjugation with triphenylphosphonium cation
title Efflux pump-mediated resistance to antifungal compounds can be prevented by conjugation with triphenylphosphonium cation
title_full Efflux pump-mediated resistance to antifungal compounds can be prevented by conjugation with triphenylphosphonium cation
title_fullStr Efflux pump-mediated resistance to antifungal compounds can be prevented by conjugation with triphenylphosphonium cation
title_full_unstemmed Efflux pump-mediated resistance to antifungal compounds can be prevented by conjugation with triphenylphosphonium cation
title_short Efflux pump-mediated resistance to antifungal compounds can be prevented by conjugation with triphenylphosphonium cation
title_sort efflux pump-mediated resistance to antifungal compounds can be prevented by conjugation with triphenylphosphonium cation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6269435/
https://www.ncbi.nlm.nih.gov/pubmed/30504815
http://dx.doi.org/10.1038/s41467-018-07633-9
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