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Azole Antifungal Agents To Treat the Human Pathogens Acanthamoeba castellanii and Acanthamoeba polyphaga through Inhibition of Sterol 14α-Demethylase (CYP51)

David Lamb Orcid Logo, Andrew Warrilow, Nicola J. Rolley, Josie Parker, W. David Nes, Stephen N. Smith, Diane Kelly, Steven Kelly Orcid Logo

Antimicrobial Agents and Chemotherapy, Volume: 59, Issue: 8, Pages: 4707 - 4713

Swansea University Authors: David Lamb Orcid Logo, Andrew Warrilow, Josie Parker, Diane Kelly, Steven Kelly Orcid Logo

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DOI (Published version): 10.1128/AAC.00476-15

Abstract

Herein, we have investigated the amebicidal activities of the pharmaceutical triazole CYP51 inhibitors fluconazole, itraconazole, and voriconazole against Acanthamoeba castellanii and Acanthamoeba polyphaga and assess their potential as therapeutic agents against Acanthamoeba infections in humans. A...

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Published in: Antimicrobial Agents and Chemotherapy
ISSN: 0066-4804 1098-6596
Published: 2015
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URI: https://cronfa.swan.ac.uk/Record/cronfa31514
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spelling 2019-05-30T10:42:29.1464531 v2 31514 2016-12-18 Azole Antifungal Agents To Treat the Human Pathogens Acanthamoeba castellanii and Acanthamoeba polyphaga through Inhibition of Sterol 14α-Demethylase (CYP51) 1dc64e55c2c28d107ef7c3db984cccd2 0000-0001-5446-2997 David Lamb David Lamb true false f066e233e8d0136c9f547b86fa43747f Andrew Warrilow Andrew Warrilow true false e563ed4e1c7db8d1e131fb78a5f8d0d5 Josie Parker Josie Parker true false 5ccf81e5d5beedf32ef8d7c3d7ac6c8c Diane Kelly Diane Kelly true false b17cebaf09b4d737b9378a3581e3de93 0000-0001-7991-5040 Steven Kelly Steven Kelly true false 2016-12-18 BMS Herein, we have investigated the amebicidal activities of the pharmaceutical triazole CYP51 inhibitors fluconazole, itraconazole, and voriconazole against Acanthamoeba castellanii and Acanthamoeba polyphaga and assess their potential as therapeutic agents against Acanthamoeba infections in humans. Amebicidal activities of the triazoles were assessed by in vitro minimum inhibition concentration (MIC) determinations using trophozoites of A. castellanii and A. polyphaga. In addition, triazole effectiveness was assessed by ligand binding studies and inhibition of CYP51 activity of purified A. castellanii CYP51 (AcCYP51) that was heterologously expressed in Escherichia coli. Itraconazole and voriconazole bound tightly to AcCYP51 (dissociation constant [Kd] of 10 and 13 nM), whereas fluconazole bound weakly (Kd of 2,137 nM). Both itraconazole and voriconazole were confirmed to be strong inhibitors of AcCYP51 activity (50% inhibitory concentrations [IC50] of 0.23 and 0.39 μM), whereas inhibition by fluconazole was weak (IC50, 30 μM). However, itraconazole was 8- to 16-fold less effective (MIC, 16 mg/liter) at inhibiting A. polyphaga and A. castellanii cell proliferation than voriconazole (MIC, 1 to 2 mg/liter), while fluconazole did not inhibit Acanthamoeba cell division (MIC, >64 mg/liter) in vitro. Voriconazole was an effective inhibitor of trophozoite proliferation for A. castellanii and A. polyphaga; therefore, it should be evaluated in trials versus itraconazole for controlling Acanthamoeba infections. Journal Article Antimicrobial Agents and Chemotherapy 59 8 4707 4713 0066-4804 1098-6596 Acanthamoeba; cytochrome P450; azole antifungal; inhibition; chemotherapy 1 8 2015 2015-08-01 10.1128/AAC.00476-15 http://aac.asm.org/content/59/8/4707.full.pdf+html COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University 2019-05-30T10:42:29.1464531 2016-12-18T17:08:15.1612447 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine David Lamb 0000-0001-5446-2997 1 Andrew Warrilow 2 Nicola J. Rolley 3 Josie Parker 4 W. David Nes 5 Stephen N. Smith 6 Diane Kelly 7 Steven Kelly 0000-0001-7991-5040 8
title Azole Antifungal Agents To Treat the Human Pathogens Acanthamoeba castellanii and Acanthamoeba polyphaga through Inhibition of Sterol 14α-Demethylase (CYP51)
spellingShingle Azole Antifungal Agents To Treat the Human Pathogens Acanthamoeba castellanii and Acanthamoeba polyphaga through Inhibition of Sterol 14α-Demethylase (CYP51)
David Lamb
Andrew Warrilow
Josie Parker
Diane Kelly
Steven Kelly
title_short Azole Antifungal Agents To Treat the Human Pathogens Acanthamoeba castellanii and Acanthamoeba polyphaga through Inhibition of Sterol 14α-Demethylase (CYP51)
title_full Azole Antifungal Agents To Treat the Human Pathogens Acanthamoeba castellanii and Acanthamoeba polyphaga through Inhibition of Sterol 14α-Demethylase (CYP51)
title_fullStr Azole Antifungal Agents To Treat the Human Pathogens Acanthamoeba castellanii and Acanthamoeba polyphaga through Inhibition of Sterol 14α-Demethylase (CYP51)
title_full_unstemmed Azole Antifungal Agents To Treat the Human Pathogens Acanthamoeba castellanii and Acanthamoeba polyphaga through Inhibition of Sterol 14α-Demethylase (CYP51)
title_sort Azole Antifungal Agents To Treat the Human Pathogens Acanthamoeba castellanii and Acanthamoeba polyphaga through Inhibition of Sterol 14α-Demethylase (CYP51)
author_id_str_mv 1dc64e55c2c28d107ef7c3db984cccd2
f066e233e8d0136c9f547b86fa43747f
e563ed4e1c7db8d1e131fb78a5f8d0d5
5ccf81e5d5beedf32ef8d7c3d7ac6c8c
b17cebaf09b4d737b9378a3581e3de93
author_id_fullname_str_mv 1dc64e55c2c28d107ef7c3db984cccd2_***_David Lamb
f066e233e8d0136c9f547b86fa43747f_***_Andrew Warrilow
e563ed4e1c7db8d1e131fb78a5f8d0d5_***_Josie Parker
5ccf81e5d5beedf32ef8d7c3d7ac6c8c_***_Diane Kelly
b17cebaf09b4d737b9378a3581e3de93_***_Steven Kelly
author David Lamb
Andrew Warrilow
Josie Parker
Diane Kelly
Steven Kelly
author2 David Lamb
Andrew Warrilow
Nicola J. Rolley
Josie Parker
W. David Nes
Stephen N. Smith
Diane Kelly
Steven Kelly
format Journal article
container_title Antimicrobial Agents and Chemotherapy
container_volume 59
container_issue 8
container_start_page 4707
publishDate 2015
institution Swansea University
issn 0066-4804
1098-6596
doi_str_mv 10.1128/AAC.00476-15
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
url http://aac.asm.org/content/59/8/4707.full.pdf+html
document_store_str 0
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description Herein, we have investigated the amebicidal activities of the pharmaceutical triazole CYP51 inhibitors fluconazole, itraconazole, and voriconazole against Acanthamoeba castellanii and Acanthamoeba polyphaga and assess their potential as therapeutic agents against Acanthamoeba infections in humans. Amebicidal activities of the triazoles were assessed by in vitro minimum inhibition concentration (MIC) determinations using trophozoites of A. castellanii and A. polyphaga. In addition, triazole effectiveness was assessed by ligand binding studies and inhibition of CYP51 activity of purified A. castellanii CYP51 (AcCYP51) that was heterologously expressed in Escherichia coli. Itraconazole and voriconazole bound tightly to AcCYP51 (dissociation constant [Kd] of 10 and 13 nM), whereas fluconazole bound weakly (Kd of 2,137 nM). Both itraconazole and voriconazole were confirmed to be strong inhibitors of AcCYP51 activity (50% inhibitory concentrations [IC50] of 0.23 and 0.39 μM), whereas inhibition by fluconazole was weak (IC50, 30 μM). However, itraconazole was 8- to 16-fold less effective (MIC, 16 mg/liter) at inhibiting A. polyphaga and A. castellanii cell proliferation than voriconazole (MIC, 1 to 2 mg/liter), while fluconazole did not inhibit Acanthamoeba cell division (MIC, >64 mg/liter) in vitro. Voriconazole was an effective inhibitor of trophozoite proliferation for A. castellanii and A. polyphaga; therefore, it should be evaluated in trials versus itraconazole for controlling Acanthamoeba infections.
published_date 2015-08-01T03:38:31Z
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