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| Status |
Public on Sep 26, 2024 |
| Title |
Overcoming amphotericin B resistance in Candida auris using the antiemetic drug, rolapitant |
| Organism |
Candidozyma auris |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
The emergence of Candida auris poses a significant health challenge that has led to a new era of multidrug-resistant fungal infections. Invasive infections caused by C. auris are usually associated with remarkable morbidity and mortality. For many years, amphotericin B (AmB) remained the most efficient and the last line of treatment against most hard-to-treat fungal infections. However, strains of C. auris possess extraordinary resistance to most antifungal agents, including AmB. In this study, we screened ~2600 FDA-approved drugs and clinical compounds to identify the antiemetic drug rolapitant as a promising enhancer to AmB against C. auris. Rolapitant exhibited potent synergistic interactions with AmB against all tested (29/29) C. auris isolates. In a time-kill assay, rolapitant restored the fungicidal activity of AmB within 4 h. Additionally, the synergistic relationship between rolapitant and AmB was observed against other medically crucial Candida, Cryptococcus and Aspergillus species with Ī£FICI that ranged from 0.16 to 0.5. In a transcriptomic study, ion transporters and ATP generation were identified as primary pathways impacted in C. auris AR0390 cells exposed to rolapitant. An ATP luminescence assay confirmed that rolapitant, at sub-inhibitory concentrations, significantly interfered with ATP production in C. auris. Moreover, rolapitant enhanced the in vivo activity of AmB in a mouse model of disseminated C. auris infection, as the combination reduced the fungal burden in murine kidneys by ~1 log (~90%) colony forming units. Our findings warrant further investigation of using rolapitant to overcome AmB resistance in C. auris and other fungal species.
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| Overall design |
Samples GSM7806557, GSM7806558 and GSM7806559 from GSE244094 were used as the controls:
GSM7806557 DMSO sample 1 [A4] SRX21897801 SAMN37548903
GSM7806558 DMSO sample 2 [A5] SRX21897802 SAMN37548902
GSM7806559 DMSO sample 3 [A6] SRX21897803 SAMN37548901
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| Contributor(s) |
Salama EA, Elgammal Y, Lanman NA, Utturkar SM, Hazbun TR, Seleem MN |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
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| Submission date |
Apr 11, 2024 |
| Last update date |
Sep 26, 2024 |
| Contact name |
Sagar M Utturkar |
| E-mail(s) |
sutturka@purdue.edu
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| Organization name |
Purdue University
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| Department |
Institute for Cancer Research
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| Lab |
C3B
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| Street address |
201 S University St
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| City |
West Lafayette |
| State/province |
IN |
| ZIP/Postal code |
47906 |
| Country |
USA |
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| Platforms (1) |
| GPL28368 |
Illumina NovaSeq 6000 ([Candida] auris) |
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| Samples (3) |
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| Relations |
| Reanalysis of |
GSM7806557 |
| Reanalysis of |
GSM7806558 |
| Reanalysis of |
GSM7806559 |
| BioProject |
PRJNA1099273 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE263806_raw_counts.xlsx |
280.2 Kb |
(ftp)(http) |
XLSX |
SRA Run Selector |
| Raw data are available in SRA |
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