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Mechanisms of Action: Physiological Effects

Crystal Structures of Full-Length Lanosterol 14α-Demethylases of Prominent Fungal Pathogens Candida albicans and Candida glabrata Provide Tools for Antifungal Discovery

Mikhail V. Keniya, Manya Sabherwal, Rajni K. Wilson, Matthew A. Woods, Alia A. Sagatova, Joel D. A. Tyndall, Brian C. Monk
Mikhail V. Keniya
Sir John Walsh Research Institute, Faculty of Dentistry, University of Otago, Dunedin, New Zealand
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Manya Sabherwal
Sir John Walsh Research Institute, Faculty of Dentistry, University of Otago, Dunedin, New Zealand
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Rajni K. Wilson
Sir John Walsh Research Institute, Faculty of Dentistry, University of Otago, Dunedin, New Zealand
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Matthew A. Woods
Sir John Walsh Research Institute, Faculty of Dentistry, University of Otago, Dunedin, New Zealand
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Alia A. Sagatova
Sir John Walsh Research Institute, Faculty of Dentistry, University of Otago, Dunedin, New Zealand
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Joel D. A. Tyndall
School of Pharmacy, University of Otago, Dunedin, New Zealand
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Brian C. Monk
Sir John Walsh Research Institute, Faculty of Dentistry, University of Otago, Dunedin, New Zealand
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DOI: 10.1128/AAC.01134-18
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ABSTRACT

Targeting lanosterol 14α-demethylase (LDM) with azole drugs provides prophylaxis and treatments for superficial and disseminated fungal infections, but cure rates are not optimal for immunocompromised patients and individuals with comorbidities. The efficacy of azole drugs has also been reduced due to the emergence of drug-resistant fungal pathogens. We have addressed the need to improve the potency, spectrum, and specificity for azoles by expressing in Saccharomyces cerevisiae functional, recombinant, hexahistidine-tagged, full-length Candida albicans LDM (CaLDM6×His) and Candida glabrata LDM (CgLDM6×His) and determining their X-ray crystal structures. The crystal structures of CaLDM6×His, CgLDM6×His, and ScLDM6×His have the same fold and bind itraconazole in nearly identical conformations. The catalytic domains of the full-length LDMs have the same fold as the CaLDM6×His catalytic domain in complex with posaconazole, with minor structural differences within the ligand binding pocket. Our structures give insight into the LDM reaction mechanism and phenotypes of single-site CaLDM mutations. This study provides a practical basis for the structure-directed discovery of novel antifungals that target LDMs of fungal pathogens.

FOOTNOTES

    • Received 29 May 2018.
    • Returned for modification 27 June 2018.
    • Accepted 8 August 2018.
    • Accepted manuscript posted online 20 August 2018.
  • Supplemental material for this article may be found at https://doi.org/10.1128/AAC.01134-18.

  • Copyright © 2018 American Society for Microbiology.

All Rights Reserved.

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Crystal Structures of Full-Length Lanosterol 14α-Demethylases of Prominent Fungal Pathogens Candida albicans and Candida glabrata Provide Tools for Antifungal Discovery
Mikhail V. Keniya, Manya Sabherwal, Rajni K. Wilson, Matthew A. Woods, Alia A. Sagatova, Joel D. A. Tyndall, Brian C. Monk
Antimicrobial Agents and Chemotherapy Oct 2018, 62 (11) e01134-18; DOI: 10.1128/AAC.01134-18

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Crystal Structures of Full-Length Lanosterol 14α-Demethylases of Prominent Fungal Pathogens Candida albicans and Candida glabrata Provide Tools for Antifungal Discovery
Mikhail V. Keniya, Manya Sabherwal, Rajni K. Wilson, Matthew A. Woods, Alia A. Sagatova, Joel D. A. Tyndall, Brian C. Monk
Antimicrobial Agents and Chemotherapy Oct 2018, 62 (11) e01134-18; DOI: 10.1128/AAC.01134-18
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KEYWORDS

antifungal
cytochrome P450
lanosterol 14α-demethylase
Saccharomyces cerevisiae expression
crystal structure
fungal pathogen
Candida albicans
Candida glabrata

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