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| Status |
Public on Oct 06, 2020 |
| Title |
Potent synergistic interactions between lopinavir and azole antifungal drugs against emerging multidrug-resistant Candida auris |
| Organism |
[Candida] auris |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
The limited number of antifungals and the emergence of multidrug-resistant Candida auris pose a significant challenge to human medicine. Here, we utilized combinatorial drug therapy as an approach to augment the activity of current azole antifungals against C. auris. We evaluated the fluconazole chemosensitization activity of 1547 FDA-approved drugs and clinical molecules against an azole-resistant strain of C. auris. This led to the discovery that lopinavir, an antiviral drug, is a potent agent capable of sensitizing C. auris to the effect of azole antifungals. At a therapeutically achievable concentration (4-8 µg/ml), lopinavir exhibited potent synergistic interactions with azole drugs, particularly with itraconazole, against C. auris (ΣFICI ranged from 0.05-0.50). 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). Moreover, lopinavir enhanced the antifungal activity of itraconazole against other medically important Candida species including C. albicans, C. tropicalis, C. glabrata, C. tropicalis, and C. parapsilosis. Comparative transcriptomic profiling revealed that lopinavir interferes with glucose permeation and ATP synthesis. This compromises the function of the efflux pumps presents in C. auris enhancing sensitivity to azole antifungals, as demonstrated by Nile red efflux assays. This study presents lopinavir as a novel, potent and broad-spectrum azole chemosensitizing agent that warrants further investigation against recalcitrant Candida infections.
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| Overall design |
Method: polyA selection of mRNA from Candida auris either treated or untreated, followed by sequenced on a NovaSeq 6000
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| Contributor(s) |
Eldesouky HE, Salama EA, Lanman NA, Hazbun TR, Seleem MN |
| Citation(s) |
33046487 |
| Submission date |
Apr 08, 2020 |
| Last update date |
Jan 02, 2024 |
| Contact name |
Nadia Marie Atallah |
| Organization name |
Purdue University
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| Department |
Center for Cancer Research
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| Street address |
201 S. University St
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| City |
West Lafayette |
| State/province |
IN |
| ZIP/Postal code |
47907 |
| Country |
USA |
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| Platforms (1) |
| GPL28368 |
Illumina NovaSeq 6000 ([Candida] auris) |
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| Samples (4)
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| Relations |
| BioProject |
PRJNA623931 |
| SRA |
SRP255757 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE148341_LPV.RNAseq.genecounts.txt.gz |
126.0 Kb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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