Use of Haploid Model of Candida albicans to Uncover Mechanism of Action of a Novel Antifungal Agent

Truong, Tin; Suriyanarayanan, Tanujaa; Zeng, Guisheng; Le, Thuc Duy; Liu, Lin; Li, Jiuyong; Cao, Tong; Wang, Yan Ming; Seneviratne, Chaminda Jayampath

doi:10.3389/fcimb.2018.00164

Cited by 15 publications

(11 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…On the one hand, the antifungal effects of many compounds were confirmed to be related to the elevated endogenous ROS. Compounds with different scaffolds, such as shikonin, heterocycle thiazole compounds, clerodane type diterpene, and SM21, exhibited antifungal activity through increasing the production of ROS in fungi (Miao et al, 2012;Bhattacharya et al, 2015;de Sa et al, 2017;Truong et al, 2018). On the other hand, the induction of elevated endogenous ROS is the mechanism of many antifungal synergists.…”

Section: Discussionmentioning

confidence: 99%

A New Antifungal Agent (4-phenyl-1, 3-thiazol-2-yl) Hydrazine Induces Oxidative Damage in Candida albicans

et al. 2020

Front. Cell. Infect. Microbiol.

View full text Add to dashboard Cite

A gradual rise in immunocompromised patients over past years has led to the increasing incidence of invasive fungal infections. Development of effective fungicides can not only provide new means for clinical treatment, but also reduce the occurrence of fungal resistance. We identified a new antifungal agent (4-phenyl-1, 3-thiazol-2-yl), hydrazine (numbered as 31C) which showed high-efficiency, broad-spectrum and specific activities. The minimum inhibitory concentration of 31C against pathogenic fungi was between 0.0625-4 µg/ml in vitro, while 31C had no obvious cytotoxicity to human umbilical vein endothelial cells with the concentration of 4 µg/ml. In addition, 31C of 0.5 µg/ml could exhibit significant fungicidal activity and inhibit the biofilm formation of C. albicans. In vivo fungal infection model showed that 31C of 10 mg/kg significantly increased the survival rate of Galleria mellonella. Further study revealed that 31C-treatment increased the reactive oxygen species (ROS) in C. albicans and elevated the expression of some genes related to anti-oxidative stress response, including CAP1, CTA1, TRR1, and SODs. Consistently, 31C-induced high levels of intracellular ROS resulted in considerable DNA damage, which played a critical role in antifungal-induced cellular death. The addition of ROS scavengers, such as glutathione (GSH), N-Acetyl-L-cysteine (NAC) or oligomeric proanthocyanidins (OPC), dramatically reduced the antifungal activities of 31C and rescued the 31C-induced filamentation defect. Collectively, these results showed that 31C exhibited strong antifungal activity and induced obvious oxidative damage, which indicated that compounds with a structure similar to 31C may provide new sight for antifungal drug development.

show abstract

Section: Discussionmentioning

confidence: 99%

A New Antifungal Agent (4-phenyl-1, 3-thiazol-2-yl) Hydrazine Induces Oxidative Damage in Candida albicans

et al. 2020

Front. Cell. Infect. Microbiol.

View full text Add to dashboard Cite

show abstract

“…These molecules restrict the bud to hyphal growth in C. albicans and affect multiple signaling pathways that are intricate in the filamentation process which regulates the biofilm formation (Midkiff et al, 2011;Grald et al, 2012;Pierce et al, 2015b). By screening a library of 50,240 small molecules of inhibitors for yeast-to-hypha transition, Sm21 6 was identified as a novel small antifungal molecule that showed its efficacy in both in vivo oral candidiasis mouse model and in vitro system.The study also revealed that compound 6 when given to C. albicans strain led to reactive oxygen species (ROS) accumulation and mitochondrial dysfunction (Wong et al, 2014;Truong et al, 2018). In another study, Chrysazin 7 (1, 8-dihydroxyanthraquinone) and Alizarin 8 (1, 2-dihydroxyanthraquinone) an anthraquinone derivative, effectively inhibits biofilm formation in C. albicans.…”

Section: Inhibitors Of Budded To Hyphal Transitionmentioning

confidence: 96%

Mechanistic Understanding of Candida albicans Biofilm Formation and Approaches for Its Inhibition

et al. 2021

View full text Add to dashboard Cite

In recent years, the demand for novel antifungal therapies has increased several- folds due to its potential to treat severe biofilm-associated infections. Biofilms are made by the sessile microorganisms attached to the abiotic or biotic surfaces, enclosed in a matrix of exopolymeric substances. This results in new phenotypic characteristics and intrinsic resistance from both host immune response and antimicrobial drugs. Candida albicans biofilm is a complex association of hyphal cells that are associated with both abiotic and animal tissues. It is an invasive fungal infection and acts as an important virulent factor. The challenges linked with biofilm-associated diseases have urged scientists to uncover the factors responsible for the formation and maturation of biofilm. Several strategies have been developed that could be adopted to eradicate biofilm-associated infections. This article presents an overview of the role of C. albicans biofilm in its pathogenicity, challenges it poses and threats associated with its formation. Further, it discusses strategies that are currently available or under development targeting prostaglandins, quorum-sensing, changing surface properties of biomedical devices, natural scaffolds, and small molecule-based chemical approaches to combat the threat of C. albicans biofilm. This review also highlights the recent developments in finding ways to increase the penetration of drugs into the extracellular matrix of biofilm using different nanomaterials against C. albicans.

show abstract

“…Additionally, SM21 did not exhibit antibacterial activity even at 10 times the effective concentration for fungi, akin to other antifungal agents and the Minimum Inhibitory concentration (MIC) of SM21 is comparable to that commonly used antifungals such as AmB (Wong et al, 2014). Subsequently, we identified the mechanism of action of SM21, which targets fungal-specific mitochondrial proteins (Truong et al, 2018). Moreover, no detrimental effects were observed with SM21 in a candidiasis mice model (Wong et al, 2014).…”

Section: Introductionmentioning

confidence: 97%

Predictive Nephrotoxicity Profiling of a Novel Antifungal Small Molecule in Comparison to Amphotericin B and Voriconazole

et al. 2020

Self Cite

View full text Add to dashboard Cite

Background and Purpose: Candida albicans is the major fungal species associated with superficial mucosal infections such as oral candidiasis as well as systemic mycoses with high morbidity and mortality. On top of the rising drug resistance, currently available antifungal agents have significant adverse effects. Nephrotoxicity is the major treatment complication associated with antifungal agents.Recently, we discovered a novel antifungal small molecule SM21 with promising antifungal activity. The present study aimed to comparatively evaluate the in vivo and in vitro nephrotoxicity of SM21 comparing with Amphotericin B and voriconazole. Experimental Approach: Nephrotoxicity of SM21 and its analogue were comparatively evaluated with Amphotericin B (AmB) and voriconazole. Immortalized human kidney proximal tubule epithelial cells (HK-2) were used for in vitro analysis of nephrotoxicity using cytotoxicity assays and qPCR gene expression analysis (Kim-1/HAVcr-1, CASP3). Sprague Dawley (SD) rat model was used to evaluate the nephrotoxicity in vivo using classical (SCr and BUN) and next-generation kidney injury urinary biomarkers (Kim-1, CLU, ALB, NGAL, b 2M, and Cys C) alongside histopathological and immunohistochemical standards. Key Results: AmB treatment showed a stronger cytotoxic impact on HK-2 viability and gene expression of cell death markers (Kim-1/HAVcr-1, CASP3) compared with SM21 and SM21 analogue in vitro (P < 0.01). In vivo data further demonstrated that SM21 did not significantly increase classical as well as novel nephrotoxic biomarkers, and minimal renal tubular necrosis and abnormalities were observed (15 mg kg −1 BW/day). Conclusions and Implications: SM21 had a significantly better safety profile in terms of nephrotoxicity with no major tubular epithelial abnormalities observed in kidney cells and no augmentation of kidney injury biomarkers compared to AmB. Kim-1 and CLU were the most sensitive biomarkers for detection of AmB-induced kidney damage. Future clinical

show abstract

Use of Haploid Model of Candida albicans to Uncover Mechanism of Action of a Novel Antifungal Agent

Cited by 15 publications

References 55 publications

A New Antifungal Agent (4-phenyl-1, 3-thiazol-2-yl) Hydrazine Induces Oxidative Damage in Candida albicans

A New Antifungal Agent (4-phenyl-1, 3-thiazol-2-yl) Hydrazine Induces Oxidative Damage in Candida albicans

Mechanistic Understanding of Candida albicans Biofilm Formation and Approaches for Its Inhibition

Predictive Nephrotoxicity Profiling of a Novel Antifungal Small Molecule in Comparison to Amphotericin B and Voriconazole

Contact Info

Product

Resources

About