Journal article 1733 views
Azole Antifungal Agents To Treat the Human Pathogens Acanthamoeba castellanii and Acanthamoeba polyphaga through Inhibition of Sterol 14α-Demethylase (CYP51)
,
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
Full text not available from this repository: check for access using links below.
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...
| Published in: | Antimicrobial Agents and Chemotherapy |
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| ISSN: | 0066-4804 1098-6596 |
| Published: |
2015
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| Online Access: |
Check full text
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| URI: | https://cronfa.swan.ac.uk/Record/cronfa31514 |
| 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. 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. |
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| Keywords: |
Acanthamoeba; cytochrome P450; azole antifungal; inhibition; chemotherapy |
| College: |
Faculty of Medicine, Health and Life Sciences |
| Issue: |
8 |
| Start Page: |
4707 |
| End Page: |
4713 |