Enhanced Production of Farnesol by Candida albicans Treated with Four Azoles

ABSTRACT The dimorphic fungus Candida albicans excretes farnesol, which is produced enzymatically from the sterol biosynthetic intermediate farnesyl pyrophosphate. Inhibition of C. albicans by four azole antifungals, fluconazole, ketoconazole, miconazole, and clotrimazole, caused elevated farnesol production (10- to 45-fold). Furthermore, farnesol production occurs in both laboratory strains and clinical isolates (J. M. Hornby et al., Appl. Environ. Microbiol. 67:2982-2992, 2001) of C. albicans.

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Farnesol Biosynthesis in Candida albicans: Cellular Response to Sterol Inhibition by Zaragozic Acid B

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.47.7.2366-2369.2003 ◽

2003 ◽

Vol 47 (7) ◽

pp. 2366-2369 ◽

Cited By ~ 85

Author(s):

Jacob M. Hornby ◽

Bessie W. Kebaara ◽

Kenneth W. Nickerson

Keyword(s):

Candida Albicans ◽

Cellular Response ◽

Biosynthetic Pathway ◽

Fungicidal Activity ◽

Sterol Biosynthesis ◽

Farnesyl Pyrophosphate ◽

Dimorphic Fungus ◽

Cell Extracts ◽

Antifungal Antibiotics ◽

Zaragozic Acid

ABSTRACT The dimorphic fungus Candida albicans produces farnesol as a quorum-sensing molecule that regulates cellular morphology. The biosynthetic origin of farnesol has been resolved by treating these cells with zaragozic acid B, a potent inhibitor of squalene synthase in the sterol biosynthetic pathway. Treatment with zaragozic acid B leads to an eightfold increase in the amount of farnesol produced by C. albicans. Furthermore, C. albicans cell extracts contain enzymatic activity to convert [3H]farnesyl pyrophosphate to [3H]farnesol. Many common antifungal antibiotics (e.g., zaragozic acids, azoles, and allylamines) target steps in sterol biosynthesis. We suggest that the fungicidal activity of zaragozic acid derives in large part from the accumulation of farnesol that accompanies the inhibition of sterol biosynthesis.

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Multiple resistance mechanisms to azole antifungals in yeast clinical isolates

Drug Resistance Updates ◽

10.1016/s1368-7646(98)80006-x ◽

1998 ◽

Vol 1 (4) ◽

pp. 255-265 ◽

Cited By ~ 66

Author(s):

Dominique Sanglard ◽

Françoise Ischer ◽

David Calabrese ◽

Michelle de Micheli ◽

Jacques Bille

Keyword(s):

Resistance Mechanisms ◽

Clinical Isolates ◽

Multiple Resistance ◽

Azole Antifungals

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Mechanisms of resistance to fluconazole in Candida albicans clinical isolates from Iranian HIV-infected patients with oropharyngeal candidiasis

Journal de Mycologie Médicale ◽

10.1016/j.mycmed.2015.10.007 ◽

2016 ◽

Vol 26 (1) ◽

pp. 35-41 ◽

Cited By ~ 17

Author(s):

S. Salari ◽

A.R. Khosravi ◽

S.A.A. Mousavi ◽

G.H. Nikbakht-Brojeni

Keyword(s):

Candida Albicans ◽

Clinical Isolates ◽

Oropharyngeal Candidiasis ◽

Mechanisms Of Resistance

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Pathogenicity of Candida tropicalis and Candida albicans after gastrointestinal inoculation in mice

Infection and Immunity ◽

10.1128/iai.29.2.808-813.1980 ◽

1980 ◽

Vol 29 (2) ◽

pp. 808-813 ◽

Cited By ~ 1

Author(s):

J R Wingard ◽

J D Dick ◽

W G Merz ◽

G R Sandford ◽

R Saral ◽

...

Keyword(s):

Candida Albicans ◽

Mouse Model ◽

Lung Tissue ◽

Candida Tropicalis ◽

Cytotoxic Drugs ◽

Clinical Isolates ◽

Yeast Cells ◽

Gastrointestinal Mucosa ◽

Compromised Host ◽

Adult Mice

The ability of clinical isolates of Candida albicans and candida tropicalis to invade through normal and damaged gastrointestinal mucosa was determined. Adult mice were treated with either gentamicin or gentamicin and cytarabine. Suspensions of yeast cells (10(7)) were administered through a catheter intraesophageally. Invasion was determined by culturing liver, kidney, and lung tissue from mice sacrificed after 48 h. C. albicans and C. tropicalis were incapable of invading through normal gastrointestinal mucosa in mice treated only with gentamicin. Two isolates of C. tropicalis penetrated the damaged gastrointestinal mucosa in 69% (49 of 71) of mice treated with gentamicin and cytarabine. In contrast, three isolates of C. albicans penetrated he damaged gastrointestinal mucosa in only 23% (14 of 62) of mice. These results suggest that C. tropicalis is more capable of invading through damaged gastrointestinal mucosa than C. albicans. The observations in this mouse model parallel those seen in patients on cytotoxic drugs. Therefore, this model offers a tool for investigation of the pathogenicity of these organisms in a model analogous to the compromised host.

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Phagocytes from Mice Lacking the Sts Phosphatases Have an Enhanced Antifungal Response to Candida albicans

mBio ◽

10.1128/mbio.00782-18 ◽

2018 ◽

Vol 9 (4) ◽

Cited By ~ 8

Author(s):

David Frank ◽

Shamoon Naseem ◽

Gian Luigi Russo ◽

Cindy Li ◽

Kaustubh Parashar ◽

...

Keyword(s):

Bone Marrow ◽

Immune Response ◽

Candida Albicans ◽

Tyrosine Kinase ◽

Critical Role ◽

Inflammasome Activation ◽

Wild Type ◽

Content Type ◽

Enhanced Production ◽

Immunological Mechanisms

ABSTRACT Mice lacking expression of the homologous phosphatases Sts-1 and Sts-2 (Sts−/− mice) are resistant to disseminated candidiasis caused by the fungal pathogen Candida albicans. To better understand the immunological mechanisms underlying the enhanced resistance of Sts−/− mice, we examined the kinetics of fungal clearance at early time points. In contrast to the rapid C. albicans growth seen in normal kidneys during the first 24 h postinfection, we observed a reduction in kidney fungal CFU within Sts−/− mice beginning at 12 to 18 h postinfection. This corresponds to the time period when large numbers of innate leukocytes enter the renal environment to counter the infection. Because phagocytes of the innate immune system are important for host protection against pathogenic fungi, we evaluated responses of bone marrow leukocytes. Relative to wild-type cells, Sts−/− marrow monocytes and bone marrow-derived dendritic cells (BMDCs) displayed a heightened ability to inhibit C. albicans growth ex vivo. This correlated with significantly enhanced production of reactive oxygen species (ROS) by Sts−/− BMDCs downstream of Dectin-1, a C-type lectin receptor that plays a critical role in stimulating host responses to fungi. We observed no visible differences in the responses of other antifungal effector pathways, including cytokine production and inflammasome activation, despite enhanced activation of the Syk tyrosine kinase downstream of Dectin-1 in Sts−/− cells. Our results highlight a novel mechanism regulating the immune response to fungal infections. Further understanding of this regulatory pathway could aid the development of therapeutic approaches to enhance protection against invasive candidiasis. IMPORTANCE Systemic candidiasis caused by fungal Candida species is becoming an increasingly serious medical problem for which current treatment is inadequate. Recently, the Sts phosphatases were established as key regulators of the host antifungal immune response. In particular, genetic inactivation of Sts significantly enhanced survival of mice infected intravenously with Candida albicans. The Sts−/− in vivo resistance phenotype is associated with reduced fungal burden and an absence of inflammatory lesions. To understand the underlying mechanisms, we studied phagocyte responses. Here, we demonstrate that Sts−/− phagocytes have heightened responsiveness to C. albicans challenge relative to wild-type cells. Our data indicate the Sts proteins negatively regulate phagocyte activation via regulating selective elements of the Dectin-1–Syk tyrosine kinase signaling axis. These results suggest that phagocytes lacking Sts respond to fungal challenge more effectively and that this enhanced responsiveness partially underlies the profound resistance of Sts−/− mice to systemic fungal challenge.

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Comparison of 3 Alcohol Gels and 70% Ethyl Alcohol for Hand Hygiene

Infection Control and Hospital Epidemiology ◽

10.1086/591092 ◽

2008 ◽

Vol 29 (10) ◽

pp. 960-962 ◽

Cited By ~ 6

Author(s):

Mirian Nicéa Zarpellon ◽

Vanessa Sarto Soares ◽

Natal Rodrigo Albrecht ◽

Douglas Ricardo da Silva Bergamasco ◽

Lourdes Botelho Garcia ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Candida Albicans ◽

Hand Hygiene ◽

Serratia Marcescens ◽

Ethyl Alcohol ◽

Laboratory Study ◽

Clinical Isolates ◽

Methicillin Resistant ◽

Human Volunteers

In a laboratory study, we demonstrated that 3 alcohol-based hand gels, commercially available in Brazil, were as effective as the traditional 70% ethyl alcohol (by weight) in removing clinical isolates of methicillin-resistant Staphylococcus aureus, Serratia marcescens, and Candida albicans from heavily contaminated hands of human volunteers.

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Denture Stomatitis: Report of a Case with Rarely Used Treatment Modality and Review of Literature

International Healthcare Research Journal ◽

10.26440/ihrj/0405.08029 ◽

2020 ◽

Vol 4 (5) ◽

pp. 116-119

Author(s):

Parul Uppal Malhotra ◽

Neera Ohri ◽

Yagyeshwar Malhotra ◽

Anindita Mallik

Keyword(s):

Candida Albicans ◽

Candida Species ◽

Fungal Infections ◽

Bacterial Colonization ◽

Oral Candidiasis ◽

Clinical Signs ◽

Fungal Growth ◽

Dimorphic Fungus ◽

Denture Stomatitis ◽

Microbial Invasion

Candida albicans is the most common Candida species isolated from the oral cavity both in healthy and diseased. Candida albicans is a dimorphic fungus existing both in blastopore phase (yeast phase) and the hyphal or mycelial phase. Although these organisms typically colonize mucocutaneous surfaces, the latter can be portals of entry into deeper tissues when host defences are compromised. Denture stomatitis is a common form of oral candidiasis that manifests as a diffuse inflammation of the maxillary denture bearing areas & is associated with angular cheilitis. At least 70% of individuals with clinical signs of denture stomatitis exhibit fungal growth & these conditions most likely result from yeast colonization of the oral mucosa combined with Bacterial colonization. Candida species act as an endogenous infecting agent on tissue predisposed by chronic trauma to microbial invasion. At one time, oral fungal infections were rare findings in general dentist's office. They were more commonly seen in hospitalized and severely debilitated patients. However with enhanced medical and pharmaceutical technology, increasing numbers of ambulatory immunosuppressed individuals with oral fungal infections are seeking out general dentists for diagnosis and treatment of these lesions.

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Potential effect of 2-isopropyl-5-methylphenol (thymol) alone and in combination with fluconazole against clinical isolates of Candida albicans, C. glabrata and C. krusei

Journal de Mycologie Médicale ◽

10.1016/j.mycmed.2018.04.002 ◽

2018 ◽

Vol 28 (2) ◽

pp. 294-299 ◽

Cited By ~ 7

Author(s):

A. Sharifzadeh ◽

A.R. Khosravi ◽

H. Shokri ◽

H. Shirzadi

Keyword(s):

Candida Albicans ◽

Potential Effect ◽

Clinical Isolates

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Robust, Comprehensive Molecular, and Phenotypical Characterisation of Atypical Candida albicans Clinical Isolates From Bogotá, Colombia

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2020.571147 ◽

2020 ◽

Vol 10 ◽

Author(s):

Giovanni Rodríguez-Leguizamón ◽

Andrés Ceballos-Garzón ◽

Carlos F. Suárez ◽

Manuel A. Patarroyo ◽

Claudia M. Parra-Giraldo

Keyword(s):

Candida Albicans ◽

Galleria Mellonella ◽

Opportunistic Pathogen ◽

Clinical Isolates ◽

High Genetic Diversity ◽

Cluster Membership ◽

Protein Mass ◽

Molecular Tests ◽

Well Differentiated ◽

Clade 1

Candida albicans is commensal in human microbiota and is known to be the commonest opportunistic pathogen, having variable clinical outcomes that can lead to up to 60% mortality. Such wide clinical behaviour can be attributed to its phenotypical plasticity and high genetic diversity. This study characterised 10 Colombian clinical isolates which had already been identified as C. albicans by molecular tests; however, previous bioinformatics analysis of protein mass spectra and phenotypical characteristics has shown that this group of isolates has atypical behaviour, sharing characteristics of both C. africana and C. albicans. This study was aimed at evaluating atypical isolates’ pathogenic capability in the Galleria mellonella model; susceptibility profiles were determined and MLST was used for molecular characterisation. Cluster analysis, enabling unbiased bootstrap to classify the isolates and establish their cluster membership and e-BURST, was used for establishing clonal complexes (CC). Both approaches involved using representative MLST data from the 18 traditional C. albicans clades, as well as C. albicans-associated and minor species. Ten atypical isolates were distributed as follows: 6/10 (B71, B41, B60, R6, R41, and R282) were grouped into a statistically well-supported atypical cluster (AC) and constituted a differentiated CC 6; 2/10 of the isolates were clearly grouped in clade 1 and were concurrent in CC 4 (B80, B44). Another 2/10 atypical isolates were grouped in clade 10 and concurred in CC 7 (R425, R111); most atypical isolates were related to geographically distant isolates and some represented new ST. Isolates B41 and R41 in the AC had greater virulence. Isolate B44 was fluconazole-resistant and was grouped in clade 1. The atypical nature of the isolates studied here was demonstrated by the contrast between phenotypical traits (C. africana-like), molecular markers (C. albicans-like), virulence, and antifungal resistance, highlighting the widely described genetic plasticity for this genus. Our results showed that the atypical isolates forming well-differentiated groups belonged to C. albicans. Our findings could contribute towards developing molecular epidemiology approaches for managing hospital-acquired infection.

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