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

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

doi:10.1128/AAC.00476-15

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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

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

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

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

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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
Online Access:	Check full text
URI:	https://cronfa.swan.ac.uk/Record/cronfa31514

first_indexed	2016-12-18T20:56:25Z
last_indexed	2019-06-05T10:19:56Z
id	cronfa31514
recordtype	SURis
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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 Steven Kelly Steven Kelly true false 2016-12-18 MEDS 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 Medical School COLLEGE CODE MEDS 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 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	2015-08-01T07:04:08Z
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score	11.04748

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

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