|
| Status |
Public on May 13, 2024 |
| Title |
Small molecule inhibitors of fungal ∆(9) fatty acid desaturase as antifungal agent against Candida auris |
| Organisms |
Candida albicans SC5314; Candidozyma auris |
| Experiment type |
Expression profiling by high throughput sequencing
Other
|
| Summary |
Candida auris has emerged as a significant healthcare-associated pathogen, posing a serious challenge due to its multidrug-resistant nature. Given the pre-existing constraints in the discovery and provision of new antifungals, there is thus an urgent imperative to design effective strategies to tackle this pressing global concern. Here, we screened a chemical library and identified phenyl-carbohydrazide derivatives with potent activity against both C. auris and the most prevalent human fungal pathogen, C. albicans. SPB00525 (N'-(2,6-Dichlorophenyl)-5-nitro-2-furohydrazide) exhibited potent activity against different strains that were resistant to standard antifungals. Using drug-induced haploinsufficient profiling, transcriptomics and metabolomic analysis, we uncovered that Ole1, a ∆(9) fatty acid desaturase, is most likely the target of SPB00525. We also found that another SPB00525 analog, HTS06170 (N'-(2,6-Dichlorophenyl)-4-methyl-1,2,3-thiadiazole-5-carbohydrazide) had a superior antifungal activity against both C. auris and C. albicans. Both SPB00525 and HTS06170 act as antivirulence agents and inhibited the invasive hyphal growth and biofilm formation of C. albicans. SPB00525 and HTS06170 attenuated fungal damage to human enterocytes and ameliorate survival of Galleria mellonella larvae used as a model of systemic candidiasis. These data, suggest that inhibiting ∆(9) fatty acid desaturase activity represents a potential therapeutic approach for treating fungal infection caused by the superbug C. auris and the most prevalent human fungal pathogen, C. albicans.
|
| |
|
| Overall design |
In this study, we used RNA-seq to identify transcripts modulated by exposure to a novel antifungal molecule (SPB00525) in two human fungal pathogens: Candida auris and C. albicans. We also used drug-induced haploinsufficient profiling to capture the potential target(s) of SPB00525.
|
| Web link |
https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2024.1434939/full
|
| |
|
| Contributor(s) |
Sellam A, Tebbji F, Menon AC, Khemiri I, St-Cyr D, Vincent AT |
| Citation(s) |
39282497 |
| |
| Submission date |
May 08, 2024 |
| Last update date |
Sep 19, 2024 |
| Contact name |
Adnane Sellam |
| E-mail(s) |
[email protected]
|
| Organization name |
University Laval
|
| Street address |
2705 Laurier Blvd.
|
| City |
Quebec city |
| ZIP/Postal code |
G1V 4G2 |
| Country |
Canada |
| |
|
| Platforms (3) |
| GPL28368 |
Illumina NovaSeq 6000 ([Candida] auris) |
| GPL33190 |
Illumina NovaSeq 6000 (Candida albicans SC5314) |
| GPL34459 |
Illumina MiSeq (Candida albicans SC5314) |
|
| Samples (24)
|
|
| Relations |
| BioProject |
PRJNA1109421 |
Less...
More...