Identification of triazenyl indoles as inhibitors of fungal fatty acid biosynthesis with broad-spectrum activity

Iyer, Kali R.; Li, Sheena C.; Revie, Nicole M.; Lou, Jennifer W.; Duncan, Dustin; Fallah, Shafagh; Sánchez, Hiram; Skulska, Iwona; Ušaj, Mojca Mattiazzi; Safizadeh, Hamid; Larsen, Brett; Wong, Cassandra; Aman, Ahmed; Kiyota, Taira; Yoshimura, Mami; Kimura, Hiromi; Hirano, Hiroyuki; Yoshida, Minoru; Osada, Hiroyuki; Gingras, Anne‐Claude; Andes, David R.; Shapiro, Rebecca; Robbins, Nicole; Mazhab-Jafari, Mohammad T.; Whitesell, Luke; Yashiroda, Yoko; Boone, Charles; Cowen, Leah E.

doi:10.1016/j.chembiol.2023.06.005

“…Chemical genomics analysis using S. cerevisiae mutant libraries was conducted as described 58,97 . The libraries include temperature-sensitive (TS), overexpression (MoBY), and diploid heterozygous deletion (HET) collections.…”

Section: Methodsmentioning

confidence: 99%

Brilacidin, a novel antifungal agent againstCryptococcus neoformans

Diehl,

Pinzan,

de Castro

et al. 2024

Preprint

Self Cite

0

View full text Add to dashboard Cite

Cryptococcus neoformanscauses cryptococcosis, one of the most prevalent fungal diseases, generally characterized by meningitis. There is a limited and not very effective number of drugs available to combat this disease. In this manuscript, we show the host defense peptide mimetic brilacidin (BRI) as a promising antifungal drug againstC. neoformans. BRI is able to affect the organization of the cell membrane, increasing fungal cell permeability. We also investigated the effects of BRI against the model systemSaccharomyces cerevisiaeby analyzing libraries of mutants grown in the presence of BRI. InS. cerevisiae, BRI also affects the cell membrane organization, but in addition the cell wall integrity pathway and calcium metabolism. In vivo experiments show BRI significantly reducesC. neoformanssurvival inside macrophages and partially clearsC. neoformanslung infection in an immunocompetent murine model of invasive pulmonary cryptococcosis. We also observed that BRI interacts with caspofungin (CAS) and amphotericin (AmB), potentiating their mechanism of action againstC. neoformans. BRI+CAS affects endocytic movement, calcineurin, and mitogen activated protein kinases. Our results indicate that BRI is a novel antifungal drug against cryptococcosis.

show abstract

“…The measurement of antifungal susceptibility was conducted using a dose–response method as previously described ( Iyer et al, 2023 ; Revie et al, 2022 ), utilizing 96-well microtitre plates. In brief, dose–response tests were conducted using twofold serial dilutions of FLC (MedChemExpress), KTC (MedChemExpress), or 5-FC (MedChemExpress) in a final volume of 100 µl.…”

Section: Methodsmentioning

confidence: 99%

Interplay between acetylation and ubiquitination of imitation switch chromatin remodeler Isw1 confers multidrug resistance in Cryptococcus neoformans

Meng,

Ni,

Li

et al. 2024

eLife

2

0

View full text Add to dashboard Cite

Cryptococcus neoformans poses a threat to human health, but anticryptococcal therapy is hampered by the emergence of drug resistance, whose underlying mechanisms remain poorly understood. Herein, we discovered that Isw1, an imitation switch chromatin remodeling ATPase, functions as a master modulator of genes responsible for in vivo and in vitro multidrug resistance in C. neoformans. Cells with the disrupted ISW1 gene exhibited profound resistance to multiple antifungal drugs. Mass spectrometry analysis revealed that Isw1 is both acetylated and ubiquitinated, suggesting that an interplay between these two modification events exists to govern Isw1 function. Mutagenesis studies of acetylation and ubiquitination sites revealed that the acetylation status of Isw1K97 coordinates with its ubiquitination processes at Isw1K113 and Isw1K441 through modulating the interaction between Isw1 and Cdc4, an E3 ligase. Additionally, clinical isolates of C. neoformans overexpressing the degradation-resistant ISW1K97Q allele showed impaired drug-resistant phenotypes. Collectively, our studies revealed a sophisticated acetylation-Isw1-ubiquitination regulation axis that controls multidrug resistance in C. neoformans. .

show abstract

“…Chemical genomics analysis using S. cerevisiae mutant libraries was conducted as described ( 58 , 95 ). The libraries include temperature-sensitive (TS), overexpression (MoBY), and diploid heterozygous deletion (HET) collections.…”

Section: Methodsmentioning

confidence: 99%

Brilacidin, a novel antifungal agent against Cryptococcus neoformans

Diehl,

Pinzan,

de Castro

et al. 2024

mBio

Self Cite

1

0

View full text Add to dashboard Cite

Cryptococcus neoformans causes cryptococcosis, one of the most prevalent fungal diseases, generally characterized by meningitis. There is a limited and not very effective number of drugs available to combat this disease. In this manuscript, we show the host defense peptide mimetic brilacidin (BRI) as a promising antifungal drug against C. neoformans . BRI can affect the organization of the cell membrane, increasing the fungal cell permeability. We also investigated the effects of BRI against the model system Saccharomyces cerevisiae by analyzing libraries of mutants grown in the presence of BRI. In S. cerevisiae , BRI also affects the cell membrane organization, but in addition the cell wall integrity pathway and calcium metabolism. In vivo experiments show BRI significantly reduces C. neoformans survival inside macrophages and partially clears C. neoformans lung infection in an immunocompetent murine model of invasive pulmonary cryptococcosis. We also observed that BRI interacts with caspofungin (CAS) and amphotericin (AmB), potentiating their mechanism of action against C. neoformans . BRI + CAS affects endocytic movement, calcineurin, and mitogen-activated protein kinases. Our results indicate that BRI is a novel antifungal drug against cryptococcosis. IMPORTANCE Invasive fungal infections have a high mortality rate causing more deaths annually than tuberculosis or malaria. Cryptococcosis, one of the most prevalent fungal diseases, is generally characterized by meningitis and is mainly caused by two closely related species of basidiomycetous yeasts, Cryptococcus neoformans and Cryptococcus gattii . There are few therapeutic options for treating cryptococcosis, and searching for new antifungal agents against this disease is very important. Here, we present brilacidin (BRI) as a potential antifungal agent against C. neoformans . BRI is a small molecule host defense peptide mimetic that has previously exhibited broad-spectrum immunomodulatory/anti-inflammatory activity against bacteria and viruses. BRI alone was shown to inhibit the growth of C. neoformans , acting as a fungicidal drug, but surprisingly also potentiated the activity of caspofungin (CAS) against this species. We investigated the mechanism of action of BRI and BRI + CAS against C. neoformans . We propose BRI as a new antifungal agent against cryptococcosis.

show abstract

Identification of triazenyl indoles as inhibitors of fungal fatty acid biosynthesis with broad-spectrum activity

Cited by 7 publications

References 82 publications

Brilacidin, a novel antifungal agent againstCryptococcus neoformans

Brilacidin, a novel antifungal agent againstCryptococcus neoformans

Interplay between acetylation and ubiquitination of imitation switch chromatin remodeler Isw1 confers multidrug resistance in Cryptococcus neoformans

Brilacidin, a novel antifungal agent against Cryptococcus neoformans

Contact Info

Product

Resources

About