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Experimental Therapeutics

Potent Synergistic Interactions between Lopinavir and Azole Antifungal Drugs against Emerging Multidrug-Resistant Candida auris

Hassan E. Eldesouky, Ehab A. Salama, Nadia A. Lanman, Tony R. Hazbun, Mohamed N. Seleem
Hassan E. Eldesouky
aDepartment of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, Indiana, USA
bDepartment of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA
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Ehab A. Salama
aDepartment of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, Indiana, USA
bDepartment of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA
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Nadia A. Lanman
aDepartment of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, Indiana, USA
cPurdue University Center for Cancer Research, Purdue University, West Lafayette, Indiana, USA
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Tony R. Hazbun
dDepartment of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana, USA
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Mohamed N. Seleem
aDepartment of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, Indiana, USA
bDepartment of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA
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  • ORCID record for Mohamed N. Seleem
DOI: 10.1128/AAC.00684-20
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ABSTRACT

The limited therapeutic options and the recent emergence of multidrug-resistant Candida species present a significant challenge to human medicine and underscore the need for novel therapeutic approaches. Drug repurposing appears as a promising tool to augment the activity of current azole antifungals, especially against multidrug-resistant Candida auris. In this study, we evaluated the fluconazole chemosensitization activities of 1,547 FDA-approved drugs and clinical molecules against azole-resistant C. auris. This led to the discovery that lopinavir, an HIV protease inhibitor, is a potent agent capable of sensitizing C. auris to the effect of azole antifungals. At a therapeutically achievable concentration, lopinavir exhibited potent synergistic interactions with azole drugs, particularly with itraconazole against C. auris (fractional inhibitory concentration index [ΣFICI] ranged from 0.04 to 0.09). Additionally, the lopinavir/itraconazole combination enhanced the survival rate of C. auris-infected Caenorhabditis elegans by 90% and reduced the fungal burden in infected nematodes by 88.5% (P < 0.05) relative to that of the untreated control. Furthermore, lopinavir enhanced the antifungal activity of itraconazole against other medically important Candida species, including C. albicans, C. tropicalis, C. krusei, and C. parapsilosis. Comparative transcriptomic profiling and mechanistic studies revealed that lopinavir was able to significantly interfere with the glucose permeation and ATP synthesis. This compromised the efflux ability of C. auris and consequently enhanced the susceptibility to azole drugs, as demonstrated by Nile red efflux assays. Altogether, these findings present lopinavir as a novel, potent, and broad-spectrum azole-chemosensitizing agent that warrants further investigation against recalcitrant Candida infections.

FOOTNOTES

    • Received 18 April 2020.
    • Returned for modification 11 August 2020.
    • Accepted 6 October 2020.
    • Accepted manuscript posted online 12 October 2020.
  • Supplemental material is available online only.

  • Copyright © 2020 American Society for Microbiology.

All Rights Reserved.

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Potent Synergistic Interactions between Lopinavir and Azole Antifungal Drugs against Emerging Multidrug-Resistant Candida auris
Hassan E. Eldesouky, Ehab A. Salama, Nadia A. Lanman, Tony R. Hazbun, Mohamed N. Seleem
Antimicrobial Agents and Chemotherapy Dec 2020, 65 (1) e00684-20; DOI: 10.1128/AAC.00684-20

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Potent Synergistic Interactions between Lopinavir and Azole Antifungal Drugs against Emerging Multidrug-Resistant Candida auris
Hassan E. Eldesouky, Ehab A. Salama, Nadia A. Lanman, Tony R. Hazbun, Mohamed N. Seleem
Antimicrobial Agents and Chemotherapy Dec 2020, 65 (1) e00684-20; DOI: 10.1128/AAC.00684-20
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KEYWORDS

HIV Protease Inhibitors
Candida auris
glucose transporters
glucose-induced acidification assay
ATP bioluminescence assay
Nile red efflux assay
azole resistance

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