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Antifungal activity of azole compounds CPA18 and CPA109 against azole-susceptible and -resistant strains of Candida albicans

Elena C. Calabrese, Sabrina Castellano, Marisabella Santoriello, Cristina Sgherri, Mike F. Quartacci, Lucia Calucci, Andrew Warrilow, David C. Lamb, Steven Kelly, Ciro Milite, Ilaria Granata, Gianluca Sbardella, Giorgio Stefancich, Bruno Maresca, Amalia Porta

Journal of Antimicrobial Chemotherapy, Volume: 68, Issue: 5, Pages: 1111 - 1119

Swansea University Authors: Andrew Warrilow, Steven Kelly

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DOI (Published version): 10.1093/jac/dks506

Abstract

AbstractOBJECTIVES: In this study we investigated the in vitro fungistatic and fungicidal activities of CPA18 and CPA109, two azole compounds with original structural features, alone and in combination with fluconazole against fluconazole-susceptible and -resistant Candida albicans strains.METHODS:...

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Published in: Journal of Antimicrobial Chemotherapy
ISSN: 0305-7453 1460-2091
Published: Oxford University Press (OUP) 2013
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URI: https://cronfa.swan.ac.uk/Record/cronfa14005
first_indexed 2013-07-23T12:11:29Z
last_indexed 2021-10-30T02:25:45Z
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spelling 2021-10-29T09:57:06.2807542 v2 14005 2013-01-23 Antifungal activity of azole compounds CPA18 and CPA109 against azole-susceptible and -resistant strains of Candida albicans f066e233e8d0136c9f547b86fa43747f Andrew Warrilow Andrew Warrilow true false b17cebaf09b4d737b9378a3581e3de93 Steven Kelly Steven Kelly true false 2013-01-23 AbstractOBJECTIVES: In this study we investigated the in vitro fungistatic and fungicidal activities of CPA18 and CPA109, two azole compounds with original structural features, alone and in combination with fluconazole against fluconazole-susceptible and -resistant Candida albicans strains.METHODS: Antifungal activities were measured by MIC evaluation and time-kill studies. Azole binding analysis was performed by UV-Vis spectroscopy. Hyphal growth inhibition and filipin and propidium iodide staining assays were used for morphological analysis. An analysis of membrane lipids was also performed to gauge alterations in membrane composition and integrity. Synergism was calculated using fractional inhibitory concentration indices (FICIs). Evaluation of cytotoxicity towards murine macrophages was performed to verify selective antifungal activity.RESULTS: Even though their binding affinity to C. albicans Erg11p is comparable to that of fluconazole, CPA compounds are active against resistant strains of C. albicans with a mutation in ERG11 sequences and/or overexpressing the ABC transporter genes CDR1 and CDR2, which encode ATP-dependent efflux pumps. Moreover, CPA18 is fungistatic, even against the two resistant strains, and was found to be synergistic with fluconazole. Differently from fluconazole and other related azoles, CPA compounds induced marked changes in membrane permeability and dramatic alterations in membrane lipid composition.CONCLUSIONS: Our outcomes suggest that CPA compounds are able to overcome major mechanisms of resistance in C. albicans. Also, they are promising candidates for combination treatment that could reduce the toxicity caused by high fluconazole doses, particularly in immunocompromised patients. Journal Article Journal of Antimicrobial Chemotherapy 68 5 1111 1119 Oxford University Press (OUP) 0305-7453 1460-2091 1 5 2013 2013-05-01 10.1093/jac/dks506 COLLEGE NANME COLLEGE CODE Swansea University 2021-10-29T09:57:06.2807542 2013-01-23T13:48:20.4574585 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Elena C. Calabrese 1 Sabrina Castellano 2 Marisabella Santoriello 3 Cristina Sgherri 4 Mike F. Quartacci 5 Lucia Calucci 6 Andrew Warrilow 7 David C. Lamb 8 Steven Kelly 9 Ciro Milite 10 Ilaria Granata 11 Gianluca Sbardella 12 Giorgio Stefancich 13 Bruno Maresca 14 Amalia Porta 15
title Antifungal activity of azole compounds CPA18 and CPA109 against azole-susceptible and -resistant strains of Candida albicans
spellingShingle Antifungal activity of azole compounds CPA18 and CPA109 against azole-susceptible and -resistant strains of Candida albicans
Andrew Warrilow
Steven Kelly
title_short Antifungal activity of azole compounds CPA18 and CPA109 against azole-susceptible and -resistant strains of Candida albicans
title_full Antifungal activity of azole compounds CPA18 and CPA109 against azole-susceptible and -resistant strains of Candida albicans
title_fullStr Antifungal activity of azole compounds CPA18 and CPA109 against azole-susceptible and -resistant strains of Candida albicans
title_full_unstemmed Antifungal activity of azole compounds CPA18 and CPA109 against azole-susceptible and -resistant strains of Candida albicans
title_sort Antifungal activity of azole compounds CPA18 and CPA109 against azole-susceptible and -resistant strains of Candida albicans
author_id_str_mv f066e233e8d0136c9f547b86fa43747f
b17cebaf09b4d737b9378a3581e3de93
author_id_fullname_str_mv f066e233e8d0136c9f547b86fa43747f_***_Andrew Warrilow
b17cebaf09b4d737b9378a3581e3de93_***_Steven Kelly
author Andrew Warrilow
Steven Kelly
author2 Elena C. Calabrese
Sabrina Castellano
Marisabella Santoriello
Cristina Sgherri
Mike F. Quartacci
Lucia Calucci
Andrew Warrilow
David C. Lamb
Steven Kelly
Ciro Milite
Ilaria Granata
Gianluca Sbardella
Giorgio Stefancich
Bruno Maresca
Amalia Porta
format Journal article
container_title Journal of Antimicrobial Chemotherapy
container_volume 68
container_issue 5
container_start_page 1111
publishDate 2013
institution Swansea University
issn 0305-7453
1460-2091
doi_str_mv 10.1093/jac/dks506
publisher Oxford University Press (OUP)
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
document_store_str 0
active_str 0
description AbstractOBJECTIVES: In this study we investigated the in vitro fungistatic and fungicidal activities of CPA18 and CPA109, two azole compounds with original structural features, alone and in combination with fluconazole against fluconazole-susceptible and -resistant Candida albicans strains.METHODS: Antifungal activities were measured by MIC evaluation and time-kill studies. Azole binding analysis was performed by UV-Vis spectroscopy. Hyphal growth inhibition and filipin and propidium iodide staining assays were used for morphological analysis. An analysis of membrane lipids was also performed to gauge alterations in membrane composition and integrity. Synergism was calculated using fractional inhibitory concentration indices (FICIs). Evaluation of cytotoxicity towards murine macrophages was performed to verify selective antifungal activity.RESULTS: Even though their binding affinity to C. albicans Erg11p is comparable to that of fluconazole, CPA compounds are active against resistant strains of C. albicans with a mutation in ERG11 sequences and/or overexpressing the ABC transporter genes CDR1 and CDR2, which encode ATP-dependent efflux pumps. Moreover, CPA18 is fungistatic, even against the two resistant strains, and was found to be synergistic with fluconazole. Differently from fluconazole and other related azoles, CPA compounds induced marked changes in membrane permeability and dramatic alterations in membrane lipid composition.CONCLUSIONS: Our outcomes suggest that CPA compounds are able to overcome major mechanisms of resistance in C. albicans. Also, they are promising candidates for combination treatment that could reduce the toxicity caused by high fluconazole doses, particularly in immunocompromised patients.
published_date 2013-05-01T12:29:07Z
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score 11.048216

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