Two New Compounds Containing Pyridinone or Triazine Heterocycles Have Antifungal Properties against Candida albicans

Candidiasis, caused by the opportunistic yeast Candida albicans, is the most common fungal infection today. Resistance of C. albicans to current antifungal drugs has emerged over the past decade leading to the need for novel antifungal agents. Our aim was to select new antifungal compounds by library-screening methods and to assess their antifungal effects against C. albicans. After screening 90 potential antifungal compounds from JUNIA, a chemical library, two compounds, 1-(4-chlorophenyl)-4-((4-chlorophenyl)amino)-3,6-dimethylpyridin-2(1H)-one (PYR) and (Z)-N-(2-(4,6-dimethoxy-1,3,5-triazin-2-yl)vinyl)-4-methoxyaniline (TRI), were identified as having potential antifungal activity. Treatment with PYR and TRI resulted in a significant reduction of C. albicans bioluminescence as well as the number of fungal colonies, indicating rapid fungicidal activity. These two compounds were also effective against clinically isolated fluconazole- or caspofungin-resistant C. albicans strains. PYR and TRI had an inhibitory effect on Candida biofilm formation and reduced the thickness of the mannan cell wall. In a Caenorhabditis elegans infection model, PYR and TRI decreased the mortality of nematodes infected with C. albicans and enhanced the expression of antimicrobial genes that promote C. albicans elimination. Overall, PYR and TRI showed antifungal properties against C. albicans by exerting fungicidal activities and enhancing the antimicrobial gene expression of Caenorhabditis elegans.

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Synergistic Antifungal Activity of Chitosan with Fluconazole against Candida albicans, Candida tropicalis, and Fluconazole-Resistant Strains

Molecules ◽

10.3390/molecules25215114 ◽

2020 ◽

Vol 25 (21) ◽

pp. 5114

Author(s):

Wei-Hsuan Lo ◽

Fu-Sheng Deng ◽

Chih-Jung Chang ◽

Ching-Hsuan Lin

Keyword(s):

Candida Albicans ◽

Antifungal Activity ◽

Candida Tropicalis ◽

Inhibitory Effect ◽

Antifungal Drugs ◽

Drug Resistant ◽

Combinational Treatment ◽

Fluconazole Resistant ◽

Resistant Strains ◽

Drug Resistant Strains

(1) Background: Few antifungal drugs are currently available, and drug-resistant strains have rapidly emerged. Thus, the aim of this study is to evaluate the effectiveness of the antifungal activity from a combinational treatment of chitosan with a clinical antifungal drug on Candida albicans and Candida tropicalis. (2) Methods: Minimum inhibitory concentration (MIC) tests, checkerboard assays, and disc assays were employed to determine the inhibitory effect of chitosan with or without other antifungal drugs on C. albicans and C. tropicalis. (3) Results: Treatment with chitosan in combination with fluconazole showed a great synergistic fungicidal effect against C. albicans and C. tropicalis, but an indifferent effect on antifungal activity when challenged with chitosan-amphotericin B or chitosan-caspofungin simultaneously. Furthermore, the combination of chitosan and fluconazole was effective against drug-resistant strains. (4) Conclusions: These findings provide strong evidence that chitosan in combination with fluconazole is a promising therapy against two Candida species and its drug-resistant strains.

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The inositol polyphosphate kinase Ipk1 transcriptionally regulates mitochondrial functions in Candida albicans

FEMS Yeast Research ◽

10.1093/femsyr/foaa050 ◽

2020 ◽

Vol 20 (6) ◽

Author(s):

Hangqi Zhu ◽

Nali Zhu ◽

Liping Peng ◽

Bing Zhang ◽

Qilin Yu ◽

...

Keyword(s):

Candida Albicans ◽

Mitochondrial Function ◽

Antifungal Drugs ◽

Infection Model ◽

Polyphosphate Kinase ◽

Inositol Polyphosphate ◽

Human Beings ◽

Respiratory Chain Complexes ◽

Cellular Processes ◽

Mitochondrial Functions

ABSTRACT Inositol polyphosphates (IPs) is an important family of signaling molecules that regulate multiple cellular processes, such as chromatin remodeling, transcription and mRNA export. Inositol polyphosphate kinases, as the critical enzymes for production and transformation of IPs, directly determine the intracellular levels of IPs and therefore are involved in many cellular processes. However, its roles in Candida albicans, the leading fungal pathogen in human beings, remain to be investigated. In this study, we identified the inositol polyphosphate kinase Ipk1 in C. albicans and found that it localizes in the nucleus. Moreover, in the ipk1Δ/Δ mutant, the activity of mitochondrial respiratory chain complexes and the mitochondrial function was severely impaired, which were associated with down-regulation of mitochondrial function-related genes revealed by transcription profiling analysis. The ipk1Δ/Δ mutant also displayed hypersensitivity to a series of environmental stresses, such as antifungal drugs, oxidants, cell wall perturbing agents and macrophage attacks, followed by attenuation of virulence in a mouse systematic infection model. These findings firstly reported the importance of inositol polyphosphate kinase Ipk1 in C. albicans, especially its role in mitochondrial function maintenance and pathogenicity.

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Candida albicans Hyphal Formation and Virulence Assessed Using a Caenorhabditis elegans Infection Model

Eukaryotic Cell ◽

10.1128/ec.00163-09 ◽

2009 ◽

Vol 8 (11) ◽

pp. 1750-1758 ◽

Cited By ~ 124

Author(s):

Read Pukkila-Worley ◽

Anton Y. Peleg ◽

Emmanouil Tampakakis ◽

Eleftherios Mylonakis

Keyword(s):

Candida Albicans ◽

Caenorhabditis Elegans ◽

Debaryomyces Hansenii ◽

Yeast Cells ◽

Infection Model ◽

Virulence Determinants ◽

Tissue Destruction ◽

C Elegans ◽

Hyphal Formation

ABSTRACT Candida albicans colonizes the human gastrointestinal tract and can cause life-threatening systemic infection in susceptible hosts. We study here C. albicans virulence determinants using the nematode Caenorhabditis elegans in a pathogenesis system that models candidiasis. The yeast form of C. albicans is ingested into the C. elegans digestive tract. In liquid media, the yeast cells then undergo morphological change to form hyphae, which results in aggressive tissue destruction and death of the nematode. Several lines of evidence demonstrate that hyphal formation is critical for C. albicans pathogenesis in C. elegans. First, two yeast species unable to form hyphae (Debaryomyces hansenii and Candida lusitaniae) were less virulent than C. albicans in the C. elegans assay. Second, three C. albicans mutant strains compromised in their ability to form hyphae (efg1Δ/efg1Δ, flo8Δ/flo8Δ, and cph1Δ/cph1Δ efg1Δ/efg1Δ) were dramatically attenuated for virulence. Third, the conditional tet-NRG1 strain, which enables the external manipulation of morphogenesis in vivo, was more virulent toward C. elegans when the assay was conducted under conditions that permit hyphal growth. Finally, we demonstrate the utility of the C. elegans assay in a screen for C. albicans virulence determinants, which identified several genes important for both hyphal formation in vivo and the killing of C. elegans, including the recently described CAS5 and ADA2 genes. These studies in a C. elegans-C. albicans infection model provide insights into the virulence mechanisms of an important human pathogen.

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Effect of antimycotic agents on the activity of aspartyl proteinases secreted by Candida albicans

Journal of Medical Microbiology ◽

10.1099/jmm.0.05048-0 ◽

2003 ◽

Vol 52 (3) ◽

pp. 247-249 ◽

Cited By ~ 18

Author(s):

Martin Schaller ◽

Nikola Krnjaic ◽

Markus Niewerth ◽

Gerald Hamm ◽

Bernhard Hube ◽

...

Keyword(s):

Candida Albicans ◽

Amphotericin B ◽

Proteinase Inhibitors ◽

Inhibitory Effect ◽

Antifungal Drugs ◽

Immunodeficiency Virus ◽

Antimycotic Agent ◽

Pepstatin A ◽

Aspartyl Proteinases

The inhibitory effect of human immunodeficiency virus (HIV) proteinase inhibitors amprenavir and saquinavir and antifungal agents terbinafine, ketoconazole, amphotericin B and ciclopiroxolamine on aspartyl proteinases (Saps) secreted by Candida albicans was tested in an in vitro spectophotometric assay. As expected, both HIV proteinase inhibitors showed a significant inhibitory effect on Sap activity, which was comparable to that of the classical aspartyl proteinase inhibitor pepstatin A (P < 0.001). Antifungal drugs such as ketoconazole, terbinafine and amphotericin B had no, or only minor, inhibitory effects on proteolytic activity. In contrast, a significant reduction in Sap activity could be demonstrated during treatment with the antifungal agent ciclopiroxolamine (P < 0.001). These results point to a multiple effect of this antimycotic agent and might explain the reduced adherence of C. albicans to human epithelial cells at subinhibitory doses.

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Increase of Virulence and Its Phenotypic Traits in Drug-Resistant Strains of Candida albicans

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01223-07 ◽

2008 ◽

Vol 52 (3) ◽

pp. 927-936 ◽

Cited By ~ 39

Author(s):

Letizia Angiolella ◽

Anna Rita Stringaro ◽

Flavia De Bernardis ◽

Brunella Posteraro ◽

Mariantonietta Bonito ◽

...

Keyword(s):

Drug Resistance ◽

Candida Albicans ◽

Biological Properties ◽

Antifungal Drugs ◽

Infection Model ◽

Phenotypic Traits ◽

Homozygous Mutation ◽

Drug Resistant ◽

Resistant Strains ◽

Drug Resistant Strains

ABSTRACT There is concern about the rise of antifungal drug resistance, but little is known about comparative biological properties and pathogenicity of drug-resistant strains. We generated fluconazole (FLC; CO23RFLC)- or micafungin (FK; CO23RFK)-resistant strains of Candida albicans by treating a FLC- and FK-susceptible strain of this fungus (CO23S) with stepwise-increasing concentrations of either drug. Molecular analyses showed that CO23RFLC had acquired markedly increased expression of the drug-resistance efflux pump encoded by the MDR1 gene, whereas CO23RFK had a homozygous mutation in the FSK1 gene. These genetic modifications did not alter to any extent the growth capacity of the drug-resistant strains in vitro, either at 28°C or at 37°C, but markedly increased their experimental pathogenicity in a systemic mouse infection model, as assessed by the overall mortality and target organ invasion. Interestingly, no apparent increase in the vaginopathic potential of the strains was observed with an estrogen-dependent rat vaginal infection. The increased pathogenicity of drug-resistant strains for systemic infection was associated with a number of biochemical and physiological changes, including (i) marked cellular alterations associated with a different expression and content of major cell wall polysaccharides, (ii) more rapid and extensive hypha formation in both liquid and solid media, and (iii) increased adherence to plastic and a propensity for biofilm formation. Overall, our data demonstrate that experimentally induced resistance to antifungal drugs, irrespective of drug family, can substantially divert C. albicans biology, affecting in particular biological properties of potential relevance for deep-seated candidiasis.

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Antifungal Activity and Potential Mechanism of 6,7, 4′-O-Triacetylscutellarein Combined With Fluconazole Against Drug-Resistant C. albicans

Frontiers in Microbiology ◽

10.3389/fmicb.2021.692693 ◽

2021 ◽

Vol 12 ◽

Author(s):

Liu-Yan Su ◽

Guang-Hui Ni ◽

Yi-Chuan Liao ◽

Liu-Qing Su ◽

Jun Li ◽

...

Keyword(s):

Antifungal Activity ◽

Signaling Pathway ◽

Treatment Method ◽

Inhibitory Effect ◽

Antifungal Drugs ◽

Infection Model ◽

Drug Resistant ◽

Mycelium Growth

The increased resistance of Candida albicans to conventional antifungal drugs poses a huge challenge to the clinical treatment of this infection. In recent years, combination therapy, a potential treatment method to overcome C. albicans resistance, has gained traction. This study assessed the effect of 6,7,4′-O-triacetylscutellarein (TA) combined with fluconazole (FLC) on C. albicans in vitro and in vivo. TA combined with FLC showed good synergistic antifungal activity against drug-resistant C. albicans in vitro, with a partial inhibitory concentration index (FICI) of 0.0188–0.1800. In addition, the time-kill curve confirmed the synergistic effect of TA and FLC. TA combined with FLC showed a strong synergistic inhibitory effect on the biofilm formation of resistant C. albicans. The combined antifungal efficacy of TA and FLC was evaluated in vivo in a mouse systemic fungal infection model. TA combined with FLC prolonged the survival rate of mice infected with drug-resistant C. albicans and reduced tissue invasion. TA combined with FLC also significantly inhibited the yeast-hypha conversion of C. albicans and significantly reduced the expression of RAS-cAMP-PKA signaling pathway-related genes (RAS1 and EFG1) and hyphal-related genes (HWP1 and ECE1). Furthermore, the mycelium growth on TA combined with the FLC group recovered after adding exogenous db-cAMP. Collectively, these results show that TA combined with FLC inhibits the formation of hyphae and biofilms through the RAS-cAMP-PKA signaling pathway, resulting in reduced infectivity and resistance of C. albicans. Therefore, this study provides a basis for the treatment of drug-resistant C. albicans infections.

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Identification of Antifungal Compounds Active against Candida albicans Using an Improved High-Throughput Caenorhabditis elegans Assay

PLoS ONE ◽

10.1371/journal.pone.0007025 ◽

2009 ◽

Vol 4 (9) ◽

pp. e7025 ◽

Cited By ~ 67

Author(s):

Ikechukwu Okoli ◽

Jeffrey J. Coleman ◽

Emmanouil Tempakakis ◽

W. Frank An ◽

Edward Holson ◽

...

Keyword(s):

Candida Albicans ◽

Caenorhabditis Elegans ◽

High Throughput ◽

Antifungal Compounds

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ISOLASI DAN IDENTIFIKASI BAKTERI ENDOFIT RIMPANG TEMULAWAK (Curcuma xanthorrhiza Roxb.) SEBAGAI PENGHASIL SENYAWA ANTIFUNGI TERHADAP Candida albicans

el–Hayah ◽

10.18860/elha.v5i2.3020 ◽

2015 ◽

Vol 5 (2) ◽

pp. 49 ◽

Cited By ~ 1

Author(s):

Alvi Milliana ◽

Wahyu Safitri

Keyword(s):

Developing Countries ◽

Candida Albicans ◽

Bioactive Compounds ◽

Endophytic Bacteria ◽

Antifungal Drugs ◽

Diffusion Method ◽

Antifungal Compounds ◽

Gram Positive ◽

Bacillus Brevis ◽

Ginger Rhizome

<em>Infectious diseases in humans by microbes in developing countries including Indonesia remains a major problem. Forty-three percent of deaths in developing countries are caused by infections. Candida is a yeast species that often cause opportunistic infections. Disease caused by Candida can affect the mouth, vagina, skin, nails, lungs, sometimes can cause septicemia, endocarditis and meningitis. Rising yeast-leavened which has resistance to antifungal compounds that exist, encourage researchers continue to discover new compounds which have antifungal properties. In addition, the side effects caused by the use of antifungal drugs, causing people still expect the natural ingredients that can be used as an alternative treatment. According to WHO, 80% of the world's population still relies on traditional medicine, including the use of drugs from plants, one of which is the use of turmeric plant (Curcuma zanthorriza). Bioactive compounds of plants that are antifungal generally are volatile oil, aldehyde and phenol compounds. The existence of endophytic microbes in plants have economic significance for the industry favorable treatment. Endophytic microbes easily grown, have a shorter life cycle than the plant and capable of producing bioactive compounds similar to the host plant. Therefore, it is necessary to study the potential of endophytic bacteria ginger rhizome (C. xanthorrhiza) as a producer of Candida albicans antifungal compounds. This study uses ginger rhizome obtained from Stone and Pasuruan. After the isolation of microbes from ginger rhizome, further purification by means of subcultures. The endophytic microbial isolates gram staining and identification of bacteria. The result is a gram-positive bacterium Actinomyces viscosus, Bacillus brevis gram-positive bacteria and gram-negative bacteria Pseudomonas stutzeri. Then do the production of antifungal metabolites produced by endophytic bacteria and C. albicans antifungal test Paper Disc Diffusion method. The result looks the inhibition zone with a diameter of 4 mm, 15 mm and 45 mm</em>

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Antifungal Properties of Nerolidol-Containing Liposomes in Association with Fluconazole

Membranes ◽

10.3390/membranes10090194 ◽

2020 ◽

Vol 10 (9) ◽

pp. 194

Author(s):

Camila Fonseca Bezerra ◽

José Geraldo de Alencar Júnior ◽

Rosilaine de Lima Honorato ◽

Antonia Thassya Lucas dos Santos ◽

Josefa Carolaine Pereira da Silva ◽

...

Keyword(s):

Candida Albicans ◽

Candida Tropicalis ◽

Water Solubility ◽

Physicochemical Characterization ◽

Inhibitory Effect ◽

Liposomal Form ◽

Antifungal Properties ◽

Fungal Dimorphism ◽

Electron Microscopy Analysis ◽

Efficient Alternative

(1) Background: Infections by Candida species represent a serious threat to the health of immunocompromised individuals. Evidence has indicated that nerolidol has significant antifungal properties. Nonetheless, its use is restricted due to a low water solubility and high photosensitivity. The incorporation into liposomes may represent an efficient alternative to improve the physicochemical and biopharmaceutical properties of this compound. The present study aimed to characterize the antifungal properties of liposomal nerolidol, alone or in combination with fluconazole. Of note, this is the first study reporting the antifungal activity of liposomal nerolidol and its potentiating effect in association with fluconazole. (2) Methods: The Inhibitory Concentration 50%-IC50 and minimum fungicide concentrations (MFC) of the substances against Candida albicans (CA), Candida tropicalis (CT), and Candida krusei (CK) were established by subculture in a solid medium. To evaluate the antifungal-enhancing effect, the MFC of fluconazole was determined in the presence or absence of subinhibitory concentrations of nerolidol (free or liposomal). The analysis of fungal dimorphism was performed through optical microscopy and the characterization of liposomes was carried out considering the vesicular size, polydispersion index, and zeta medium potential, in addition to a scanning electron microscopy analysis. (3) Results: The physicochemical characterization revealed that liposomes were obtained as homogenous populations of spherical vesicles. The data obtained in the present study indicate that nerolidol acts as an antifungal agent against Candida albicans and Candida tropicalis, in addition to potentiating (only in the liposomal form) the effect of fluconazole. However, the compound had little inhibitory effect on fungal dimorphism. (4) Conclusions: The incorporation of nerolidol into liposomes improved its antifungal-modulating properties.

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A Small Aromatic Compound Has Antifungal Properties and Potential Anti-Inflammatory Effects against Intestinal Inflammation

International Journal of Molecular Sciences ◽

10.3390/ijms20020321 ◽

2019 ◽

Vol 20 (2) ◽

pp. 321 ◽

Cited By ~ 2

Author(s):

Clovis Bortolus ◽

Muriel Billamboz ◽

Rogatien Charlet ◽

Karine Lecointe ◽

Boualem Sendid ◽

...

Keyword(s):

Intestinal Inflammation ◽

Anaerobic Bacteria ◽

Sodium Sulphate ◽

Antifungal Drugs ◽

Protective Effects ◽

Chemical Library ◽

Antifungal Properties ◽

Anti Inflammatory

Resistance of the opportunistic pathogen Candida albicans to antifungal drugs has increased significantly in recent years. After screening 55 potential antifungal compounds from a chemical library, 2,3-dihydroxy-4-methoxybenzaldehyde (DHMB) was identified as having potential antifungal activity. The properties of DHMB were then assessed in vitro and in vivo against C. albicans overgrowth and intestinal inflammation. Substitution on the aromatic ring of DHMB led to a strong decrease in its biological activity against C. albicans. The MIC of DHMB was highly effective at eliminating C. albicans when compared to that of caspofungin or fluconazole. Additionally, DHMB was also effective against clinically isolated fluconazole- or caspofungin-resistant C. albicans strains. DHMB was administered to animals at high doses. This compound was not cytotoxic and was well-tolerated. In experimental dextran sodium sulphate (DSS)-induced colitis in mice, DHMB reduced the clinical and histological score of inflammation and promoted the elimination of C. albicans from the gut. This finding was supported by a decrease in aerobic bacteria while anaerobic bacteria populations were re-established in mice treated with DHMB. DHMB is a small organic molecule with antifungal properties and anti-inflammatory activity by exerting protective effects on intestinal epithelial cells.

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