Functional genomic analysis of Candida albicans protein kinases reveals modulators of morphogenesis in diverse environments

Lee, Yunjin; Hossain, Saif; MacAlpine, Jessie; Robbins, Nicole; Cowen, Leah E.

doi:10.1016/j.isci.2023.106145

Cited by 6 publications

(4 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…albicans DSY1024 ( cdr 1Δ /cdr 1Δ cdr 2Δ /cdr 2Δ mdr 1Δ /mdr 1Δ flu 1Δ /flu 1Δ) mutant, C. albicans ire 1Δ/Δ mutant, and C. albicans hap 43Δ/Δ and C.…”

Section: Methodsmentioning

confidence: 99%

“…Strains were maintained on BBL Sabouraud dextrose agar (SDA, BD) at 35 °C in a humidified chamber for 48 h before use. The C. albicans DSY1024 ( cdr 1Δ /cdr 1Δ cdr 2Δ /cdr 2Δ mdr 1Δ /mdr 1Δ flu 1Δ /flu 1Δ) mutant, 26 C. albicans ire 1Δ/Δ mutant, 56 and C. albicans hap 43Δ/Δ and C. albicans rim 101Δ/Δ mutants 57 were obtained from previous studies. For all other assays, strains are listed in Supplemental Table S1, along with their sources.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Potent Antifungal Activity of Penta-O-galloyl-β-d-Glucose against Drug-Resistant Candida albicans, Candida auris, and Other Non-albicans Candida Species

Marquez,

Lee,

Duncan

et al. 2023

ACS Infect. Dis.

Self Cite

View full text Add to dashboard Cite

Among fungal pathogens, infections by drug-resistant Candida species continue to pose a major challenge to healthcare. This study aimed to evaluate the activity of the bioactive natural product, penta-O-galloyl-β-Dglucose (PGG) against multidrug-resistant (MDR) Candida albicans, MDR Candida auris, and other MDR non-albicans Candida species. Here, we show that PGG has a minimum inhibitory concentration (MIC) of 0.25−8 μg mL −1 (0.265−8.5 μM) against three clinical strains of C. auris and a MIC of 0.25−4 μg mL −1 (0.265−4.25 μM) against a panel of other MDR Candida species. Our cytotoxicity studies found that PGG was well tolerated by human kidney, liver, and epithelial cells with an IC 50 > 256 μg mL −1 (>272 μM). We also show that PGG is a high-capacity iron chelator and that deletion of key iron homeostasis genes in C. albicans rendered strains hypersensitive to PGG. In conclusion, PGG displayed potent anti-Candida activity with minimal cytotoxicity for human cells. We also found that the antifungal activity of PGG is mediated through an ironchelating mechanism, suggesting that the compound could prove useful as a topical treatment for superficial Candida infections.

show abstract

“…albicans DSY1024 ( cdr 1Δ /cdr 1Δ cdr 2Δ /cdr 2Δ mdr 1Δ /mdr 1Δ flu 1Δ /flu 1Δ) mutant, C. albicans ire 1Δ/Δ mutant, and C. albicans hap 43Δ/Δ and C.…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Potent Antifungal Activity of Penta-O-galloyl-β-d-Glucose against Drug-Resistant Candida albicans, Candida auris, and Other Non-albicans Candida Species

Marquez,

Lee,

Duncan

et al. 2023

ACS Infect. Dis.

Self Cite

View full text Add to dashboard Cite

show abstract

“…Another major focus was on mutants that showed altered morphology, as multiple aggregating strains have been isolated from patients ( 3 – 5 ); screening for altered morphology was the focus of two recent insertional mutagenesis screens ( 6 , 7 ). In other fungi, the interesting biological phenomena and topics of screens range from identifying regulators of sex and meiosis ( 8 ), defining essential genes ( 9 – 11 ), identifying kinases that regulate morphogenesis ( 12 ), determining modulators of host immune responses ( 13 – 15 ), or identifying new potential avenues for antifungal therapies ( 16 – 19 ), to name a few. The critical task is to define what the question is and to spend the time to justify why this is the right question to ask using a screening approach.…”

Section: What Is the Biological Question?mentioning

confidence: 99%

Going fishing: how to get what you want from a fungal genetic screen

O'Meara

2024

mSphere

View full text Add to dashboard Cite

Five years ago, as I was starting my lab, I wrote about two functional genomic screens in fungi that had inspired me (mSphere 4:e00299-19, https://doi.org/10.1128/mSphere.00299-19 ). Now, I want to discuss some of the principles and questions that I ask myself and my students as we embark on our own screens. A good screen, whether it is a genetic or chemical screen, can be the starting point for new discovery and an excellent basis for the beginning of a scientific research project. However, screens are often criticized for being “fishing expeditions.” To stretch this metaphor to the extreme, this is because people are worried that we do not know how to fish, that we will come home without any fish, bring home the wrong fish, or not know what to do with a fish if we caught it. How you set up the screen and analyze the results determines whether the screen will be useful. In this mini-review, and in the spirit of teaching a scientist to fish, I will discuss recent excellent fungal genetic and chemical screens that illustrate some of the key aspects of a successful screen.

show abstract

“…The establishment of successful infection in diverse hosts requires a wide range of virulence factors and the ability to adapt to the various environmental niches ( 3 , 5 ). The transcriptional regulation of virulence factors and fitness has been extensively studied ( 6 – 8 ); chromatin modification also regulates the commensal and pathogenic attributes of C. albicans ( 9 – 11 ). However, unlike widely studied transcriptional regulation, the role of chromatin modulation in influencing pathogenicity patterns has not been elucidated.…”

Section: Introductionmentioning

confidence: 99%

Histone deacetylase Sir2 promotes the systemic Candida albicans infection by facilitating its immune escape via remodeling the cell wall and maintaining the metabolic activity

Yang,

Li,

Zhang

et al. 2024

mBio

View full text Add to dashboard Cite

Histone deacetylation affects Candida albicans ( C. albicans ) pathogenicity by modulating virulence factor expression and DNA damage. The histone deacetylase Sir2 is associated with C. albicans plasticity and maintains genome stability to help C. albicans adapt to various environmental niches. However, whether Sir2-mediated chromatin modification affects C. albicans virulence is unclear. The purpose of our study was to investigate the effect of Sir2 on C. albicans pathogenicity and regulation. Here, we report that Sir2 is required for C. albicans pathogenicity, as its deletion affects the survival rate, fungal burden in different organs and the extent of tissue damage in a mouse model of disseminated candidiasis. We evaluated the impact of Sir2 on C. albicans virulence factors and revealed that the Sir2 null mutant had an impaired ability to adhere to host cells and was more easily recognized by the innate immune system. Comprehensive analysis revealed that the disruption of C. albicans adhesion was due to a decrease in cell surface hydrophobicity rather than the differential expression of adhesion genes on the cell wall. In addition, Sir2 affects the distribution and exposure of mannan and β-glucan on the cell wall, indicating that Sir2 plays a role in preventing the immune system from recognizing C. albicans . Interestingly, our results also indicated that Sir2 helps C. albicans maintain metabolic activity under hypoxic conditions, suggesting that Sir2 contributes to C. albicans colonization at hypoxic sites. In conclusion, our findings provide detailed insights into antifungal targets and a useful foundation for the development of antifungal drugs. IMPORTANCE Candida albicans ( C. albicans ) is the most common opportunistic fungal pathogen and can cause various superficial infections and even life-threatening systemic infections. To successfully propagate infection, this organism relies on the ability to express virulence-associated factors and escape host immunity. In this study, we demonstrated that the histone deacetylase Sir2 helps C. albicans adhere to host cells and escape host immunity by mediating cell wall remodeling; as a result, C. albicans successfully colonized and invaded the host in vivo . In addition, we found that Sir2 contributes to carbon utilization under hypoxic conditions, suggesting that Sir2 is important for C. albicans survival and the establishment of infection in hypoxic environments. In summary, we investigated the role of Sir2 in regulating C. albicans pathogenicity in detail; these findings provide a potential target for the development of antifungal drugs.

show abstract

Functional genomic analysis of Candida albicans protein kinases reveals modulators of morphogenesis in diverse environments

Cited by 6 publications

References 65 publications

Potent Antifungal Activity of Penta-O-galloyl-β-d-Glucose against Drug-Resistant Candida albicans, Candida auris, and Other Non-albicans Candida Species

Potent Antifungal Activity of Penta-O-galloyl-β-d-Glucose against Drug-Resistant Candida albicans, Candida auris, and Other Non-albicans Candida Species

Going fishing: how to get what you want from a fungal genetic screen

Histone deacetylase Sir2 promotes the systemic Candida albicans infection by facilitating its immune escape via remodeling the cell wall and maintaining the metabolic activity

Contact Info

Product

Resources

About