Lineage-specific selection and the evolution of virulence in the Candida clade

Candida albicans is the most common cause of systemic fungal infections in humans and is considerably more virulent than its closest known relative, Candida dubliniensis. To investigate this difference, we constructed interspecies hybrids and quantified mRNA levels produced from each genome in the hybrid. This approach systematically identified expression differences in orthologous genes arising from cis-regulatory sequence changes that accumulated since the two species last shared a common ancestor, some 10 million y ago. We documented many orthologous gene-expression differences between the two species, and we pursued one striking observation: All 15 genes coding for the enzymes of glycolysis showed higher expression from the C. albicans genome than the C. dubliniensis genome in the interspecies hybrid. This pattern requires evolutionary changes to have occurred at each gene; the fact that they all act in the same direction strongly indicates lineage-specific natural selection as the underlying cause. To test whether these expression differences contribute to virulence, we created a C. dubliniensis strain in which all 15 glycolysis genes were produced at modestly elevated levels and found that this strain had significantly increased virulence in the standard mouse model of systemic infection. These results indicate that small expression differences across a deeply conserved set of metabolism enzymes can play a significant role in the evolution of virulence in fungal pathogens.

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Post-Translational Modifications Drive Success and Failure of Fungal–Host Interactions

Journal of Fungi ◽

10.3390/jof7020124 ◽

2021 ◽

Vol 7 (2) ◽

pp. 124

Author(s):

Charmaine Retanal ◽

Brianna Ball ◽

Jennifer Geddes-McAlister

Keyword(s):

Fungal Pathogens ◽

Fungal Infections ◽

Treatment Options ◽

Global Scale ◽

Host Cells ◽

Candida Spp ◽

Post Translational Modifications ◽

Fungal Host ◽

Resistant Species

Post-translational modifications (PTMs) change the structure and function of proteins and regulate a diverse array of biological processes. Fungal pathogens rely on PTMs to modulate protein production and activity during infection, manipulate the host response, and ultimately, promote fungal survival. Given the high mortality rates of fungal infections on a global scale, along with the emergence of antifungal-resistant species, identifying new treatment options is critical. In this review, we focus on the role of PTMs (e.g., phosphorylation, acetylation, ubiquitination, glycosylation, and methylation) among the highly prevalent and medically relevant fungal pathogens, Candida spp., Aspergillus spp., and Cryptococcus spp. We explore the role of PTMs in fungal stress response and host adaptation, the use of PTMs to manipulate host cells and the immune system upon fungal invasion, and the importance of PTMs in conferring antifungal resistance. We also provide a critical view on the current knowledgebase, pose questions key to our understanding of the intricate roles of PTMs within fungal pathogens, and provide research opportunities to uncover new therapeutic strategies.

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Antifungal Efficacy of Marine Macroalgae against Fungal Isolates from Bronchial Asthmatic Cases

Molecules ◽

10.3390/molecules23113032 ◽

2018 ◽

Vol 23 (11) ◽

pp. 3032 ◽

Cited By ~ 14

Author(s):

Suresh Mickymaray ◽

Wael Alturaiki

Keyword(s):

Antifungal Activity ◽

Fungal Pathogens ◽

Fungal Infections ◽

Algal Species ◽

Marine Macroalgae ◽

Minimum Fungicidal Concentration ◽

Asthmatic Patients ◽

The Cost ◽

Algal Extracts ◽

Airway Colonization

Fungal sensitization is very common in bronchial asthmatic cases, and the connection with airway colonization by fungi remains uncertain. Antifungal therapy failure is a significant fraction of the cost and morbidity and mortality in the majority of the asthmatic cases. Hence, the present study aimed to investigate the antifungal activity of five marine macroalgae—Acanthaophora specifera, Cladophoropsis sp., Laurencia paniculata, Tydemania sp., and Ulva prolifera—which were tested on selected fungal pathogens isolated from 15 sputum of 45 bronchial asthmatic patients. The highest antifungal activity was observed in ethanol fractions of L. paniculata followed by U. prolifera, Cladophoropsis sp., A. specifera, and Tydemania sp. The minimum fungicidal concentration and minimum inhibitory concentration values of the ethanolic fractions of algal species were found to be 125–1000 µg/mL and 125–500 µg/mL, respectively. The algal extracts contained terpene alcohol, diterpene, steroids, sesquiterpene, and sesquiterpene alcohol, as determined by GC–MS/MS analyses. The present study shows that the marine macroalgae containing bioactive compounds had excellent inhibitory activity against a variety of fungal pathogens, which may be useful for combating fungal infections and recovering from chronic asthmatic states.

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Sterol-response pathways mediate alkaline survival in diverse fungi

10.1101/2020.03.26.010983 ◽

2020 ◽

Author(s):

Hannah E. Brown ◽

Calla L. Telzrow ◽

Joseph W. Saelens ◽

Larissa Fernandes ◽

J. Andrew Alspaugh

Keyword(s):

Fungal Pathogens ◽

Fungal Infections ◽

Membrane Integrity ◽

Microbial Pathogens ◽

Alkaline Ph ◽

Ph Response ◽

Ph Tolerance ◽

Alkaline Conditions ◽

Host Infection ◽

The Impact

AbstractThe ability for cells to maintain homeostasis in the presence of extracellular stress is essential for their survival. Stress adaptations are especially important for microbial pathogens to respond to rapidly changing conditions, such as those encountered during the transition from the environment to the infected host. Many fungal pathogens have acquired the ability to quickly adapt to changes in extracellular pH to promote their survival in the various micro-environments encountered during a host infection. For example, the fungal-specific Rim/Pal alkaline response pathway has been well characterized in many fungal pathogens, including Cryptococcus neoformans. However, alternative mechanisms for sensing and responding to host pH have yet to be extensively studied. Recent observations from a genetic screen suggest that the C. neoformans sterol homeostasis pathway is required for growth at elevated pH. This work explores interactions among mechanisms of membrane homeostasis, alkaline pH tolerance, and Rim pathway activation. We find that the sterol homeostasis pathway is necessary for growth in an alkaline environment, and that an elevated pH is sufficient to induce Sre1 activation. This pH-mediated activation of the Sre1 transcription factor is linked to the biosynthesis of ergosterol, but is not dependent on Rim pathway signaling, suggesting that these two pathways are responding to alkaline pH independently. Furthermore, we discover that C. neoformans is more susceptible to membrane-targeting antifungals in alkaline conditions highlighting the impact of micro-environmental pH on the treatment of invasive fungal infections. Together, these findings further connect membrane integrity and composition with the fungal pH response and pathogenesis.

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Candida albicans Sterol C-14 Reductase, Encoded by the ERG24 Gene, as a Potential Antifungal Target Site

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.46.4.947-957.2002 ◽

2002 ◽

Vol 46 (4) ◽

pp. 947-957 ◽

Cited By ~ 41

Author(s):

N. Jia ◽

B. Arthington-Skaggs ◽

W. Lee ◽

C. A. Pierson ◽

N. D. Lees ◽

...

Keyword(s):

Candida Albicans ◽

Fungal Pathogens ◽

Antifungal Agents ◽

Fungal Infections ◽

Brefeldin A ◽

Agricultural Applications ◽

Mouse Model System ◽

Cellular Inhibitors ◽

Germ Tubes ◽

Doubling Times

ABSTRACT The incidence of fungal infections has increased dramatically, which has necessitated additional and prolonged use of the available antifungal agents. Increased resistance to the commonly used antifungal agents, primarily the azoles, has been reported, thus necessitating the discovery and development of compounds that would be effective against the major human fungal pathogens. The sterol biosynthetic pathway has proved to be a fertile area for antifungal development, and steps which might provide good targets for novel antifungal development remain. The sterol C-14 reductase, encoded by the ERG24 gene, could be an effective target for drug development since the morpholine antifungals, inhibitors of Erg24p, have been successful in agricultural applications. The ERG24 gene of Candida albicans has been isolated by complementation of a Saccharomyces cerevisiae erg24 mutant. Both copies of the C. albicans ERG24 gene have been disrupted by using short homologous regions of the ERG24 gene flanking a selectable marker. Unlike S. cerevisiae, the C. albicans ERG24 gene was not required for growth, but erg24 mutants showed several altered phenotypes. They were demonstrated to be slowly growing, with doubling times at least twice that of the wild type. They were also shown to be significantly more sensitive to an allylamine antifungal and to selected cellular inhibitors including cycloheximide, cerulenin, fluphenazine, and brefeldin A. The erg24 mutants were also slightly resistant to the azoles. Most importantly, erg24 mutants were shown to be significantly less pathogenic in a mouse model system and failed to produce germ tubes upon incubation in human serum. On the basis of these characteristics, inhibitors of Erg24p would be effective against C. albicans.

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Fungal Infection in Cystic Fibrosis

Current Respiratory Medicine Reviews ◽

10.2174/1573398x17666210520175847 ◽

2021 ◽

Vol 17 (2) ◽

pp. 118-124

Author(s):

Amirmehdi Sarvestani ◽

Mohammad Almasian ◽

Amirhossein Nafari

Keyword(s):

Cystic Fibrosis ◽

Fungal Infection ◽

Fungal Pathogens ◽

Respiratory Infections ◽

Fungal Infections ◽

Genetic Disorder ◽

Medical Science ◽

Resistant Species ◽

Online Databases ◽

New Treatments

Background: The prevalence of fungal infections has been increasing in recent years. Cystic fibrosis (CF) is a genetic disorder that affects organs such as the intestines, liver, pancreas, and especially the lungs. Introduction: Fungal pathogens are becoming a challenge in CF. Advanced medical science is associated with longer life expectancy in some patient groups. Method: A review was conducted on studies found on online databases, including Google Scholar, PubMed, and Scopus. Internet-based searches were performed on these databases for cystic fibrosis, respiratory infections, and fungal infection profiling to identify all relevant studies published between 2010 and 2020. Result: Fungal pathogens most frequently isolated from the respiratory tract include the Aspergillus genus, the Candida genus, Scedosporium apiospermum, and the Rasamsonia genus. In cystic fibrosis, these organisms usually colonize the respiratory and intestinal tracts and cause hypersensitivity responses and invasive diseases. Conclusion: Fungus-patient interactions are complicated and depend on various factors. Moreover, the emergence of drug-resistant species is a serious health issue, and the development of new treatments is crucial.

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Identification and in Vitro Susceptibility Pattern of Fungal Pathogens in Immunocompromised Patients with invasive Fungal Infections

10.51429/ejmm30317 ◽

2021 ◽

Vol 30 (3) ◽

pp. 127-134

Author(s):

Shaimaa A.S. Selem ◽

Neveen A. Hassan ◽

Mohamed Z. Abd El-Rahman ◽

Doaa M. Abd El-Kareem

Keyword(s):

Intensive Care ◽

Fungal Infection ◽

Fungal Pathogens ◽

Fungal Infections ◽

Antifungal Susceptibility ◽

Invasive Fungal Infections ◽

Immunocompromised Patients ◽

University Hospitals ◽

Vitek 2

Background: In intensive care units, invasive fungal infections have become more common, particularly among immunocompromised patients. Early identification and starting the treatment of those patients with antifungal therapy is critical for preventing unnecessary use of toxic antifungal agents. Objective: The aim of this research is to determine which common fungi cause invasive fungal infection in immunocompromised patients, as well as their antifungal susceptibility patterns in vitro, in Assiut University Hospitals. Methodology: This was a hospital based descriptive study conducted on 120 patients with clinical suspicion of having fungal infections admitted at different Intensive Care Units (ICUs) at Assiut University Hospitals. Direct microscopic examination and inoculation on Sabouraud Dextrose Agar (SDA) were performed on the collected specimens. Isolated yeasts were classified using phenotypic methods such as chromogenic media (Brilliance Candida agar), germ tube examination, and the Vitek 2 system for certain isolates, while the identification of mould isolates was primarily based on macroscopic and microscopic characteristics. Moulds were tested in vitro for antifungal susceptibility using the disc diffusion, and yeast were tested using Vitek 2 device cards. Results: In this study, 100 out of 120 (83.3%) of the samples were positive for fungal infection. Candida and Aspergillus species were the most commonly isolated fungal pathogens. The isolates had the highest sensitivity to Amphotericin B (95 %), followed by Micafungin (94 %) in an in vitro sensitivity survey. Conclusion: Invasive fungal infections are a leading cause of morbidity and mortality in immunocompromised patients, with Candida albicans being the most frequently isolated yeast from various clinical specimens; however, the rise in resistance, especially to azoles, is a major concern.

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The importance of rapid diagnosis for multidrug-resistant Candida: an interview with Maurizio Sanguinetti

Future Microbiology ◽

10.2217/fmb-2019-0198 ◽

2019 ◽

Vol 14 (12) ◽

pp. 1011-1012

Author(s):

Maurizio Sanguinetti

Keyword(s):

Infectious Diseases ◽

Fungal Pathogens ◽

Fungal Infections ◽

Resistance Mechanisms ◽

Rapid Diagnosis ◽

Antifungal Drugs ◽

Full Professor ◽

Research Activity ◽

Diagnostic Strategies ◽

Personalized Care

In this exclusive interview, Maurizio Sanguinetti discusses current issues with Candida fungal infection diagnoses, in light of its rising resistance to antifungal drugs. This interview was conducted by Ellen Colvin, Editor of Future Microbiology. Maurizio Sanguinetti, MD, is full Professor of Microbiology at the Università Cattolica del Sacro Cuore of Rome, Italy, and Director of the Institute of Microbiology and Chief of the Department of Laboratory Sciences and Infectious Diseases Sciences at the Fondazione Policlinico Agostino Gemelli IRCCS of Rome, Italy. For several years, the research activity of Maurizio Sanguinetti has mainly focused on the development of molecular methods for the rapid diagnosis of bacterial, mycobacterial and fungal infections; the elucidation of virulence and antimicrobial resistance mechanisms in clinically relevant bacterial and fungal pathogens; the characterization of the human microbiota in relationship to infectious and noninfectious diseases and implementation of new diagnostic strategies for the personalized care of patients with infectious diseases.

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Optimization of Protective Agents for The Freeze-Drying of Paenibacillus polymyxa Kp10 as a Potential Biofungicide

Molecules ◽

10.3390/molecules25112618 ◽

2020 ◽

Vol 25 (11) ◽

pp. 2618

Author(s):

Hayatun Syamila Nasran ◽

Hidayat Mohd Yusof ◽

Murni Halim ◽

Nor’Aini Abdul Rahman

Keyword(s):

Fungal Pathogens ◽

Crop Production ◽

Freeze Drying ◽

Fungal Infections ◽

Skim Milk ◽

Paenibacillus Polymyxa ◽

Protective Agent ◽

Protective Agents ◽

Chemical Fungicides

Anthracnose is a fungal disease causing major losses in crop production. Chemical fungicides widely used in crop plantations to combat fungal infections can be a threat to the environment and humans in the long term. Recently, biofungicides have gained much interest as an alternative to chemical fungicides due to their environmentally friendly nature. Biofungicide products in powder form can be formulated using the freeze-drying technique to provide convenient storage. Protective agent formulation is needed in maintaining the optimal viable cells of biofungicide products. In this study, 8.10 log colony-forming unit (CFU)/mL was the highest cell viability of Paenibacillus polymyxa Kp10 at 22 h during incubation. The effects of several selected protective agents on the viability of P. polymyxa Kp10 after freeze-drying were studied. Response surface methodology (RSM) was used for optimizing formulation for the protective agents. The combination of lactose (10% w/v), skim milk (20% w/v), and sucrose (27.5% w/v) was found to be suitable for preserving P. polymyxa Kp10 during freeze-drying. Further, P. polymyxa Kp10 demonstrated the ability to inhibit fungal pathogens, Colletotrichum truncatum and C. gloeosporioides, at 60.18% and 66.52% of inhibition of radial growth, respectively.

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Emerging Fungal Infections: New Patients, New Patterns, and New Pathogens

Journal of Fungi ◽

10.3390/jof5030067 ◽

2019 ◽

Vol 5 (3) ◽

pp. 67 ◽

Cited By ~ 36

Author(s):

Friedman ◽

Schwartz

Keyword(s):

North America ◽

Fungal Pathogens ◽

Fungal Infections ◽

Trichophyton Mentagrophytes ◽

Invasive Fungal Disease ◽

Multidrug Resistant ◽

Antifungal Prophylaxis ◽

Candida Spp ◽

Sporothrix Brasiliensis ◽

Emerging Fungal Infections

: The landscape of clinical mycology is constantly changing. New therapies for malignant and autoimmune diseases have led to new risk factors for unusual mycoses. Invasive candidiasis is increasingly caused by non-albicans Candida spp., including C. auris, a multidrug-resistant yeast with the potential for nosocomial transmission that has rapidly spread globally. The use of mould-active antifungal prophylaxis in patients with cancer or transplantation has decreased the incidence of invasive fungal disease, but shifted the balance of mould disease in these patients to those from non-fumigatus Aspergillus species, Mucorales, and Scedosporium/Lomentospora spp. The agricultural application of triazole pesticides has driven an emergence of azole-resistant A. fumigatus in environmental and clinical isolates. The widespread use of topical antifungals with corticosteroids in India has resulted in Trichophyton mentagrophytes causing recalcitrant dermatophytosis. New dimorphic fungal pathogens have emerged, including Emergomyces, which cause disseminated mycoses globally, primarily in HIV infected patients, and Blastomyces helicus and B. percursus, causes of atypical blastomycosis in western parts of North America and in Africa, respectively. In North America, regions of geographic risk for coccidioidomycosis, histoplasmosis, and blastomycosis have expanded, possibly related to climate change. In Brazil, zoonotic sporotrichosis caused by Sporothrix brasiliensis has emerged as an important disease of felines and people.

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In Vitro Antimicrobial Activity of the Decontaminant HybenX® Compared to Chlorhexidine and Sodium Hypochlorite against Common Bacterial and Yeast Pathogens

Antibiotics ◽

10.3390/antibiotics8040188 ◽

2019 ◽

Vol 8 (4) ◽

pp. 188 ◽

Cited By ~ 3

Author(s):

Alberto Antonelli ◽

Luca Giovannini ◽

Ilaria Baccani ◽

Valentina Giuliani ◽

Riccardo Pace ◽

...

Keyword(s):

Antimicrobial Activity ◽

Sodium Hypochlorite ◽

Fungal Pathogens ◽

Antimicrobial Agents ◽

Fungal Infections ◽

Yeast Strains ◽

Low Concentrations ◽

Endodontic Infections ◽

Reference Strains

The recent increase in infections mediated by drug-resistant bacterial and fungal pathogens underlines the urgent need for novel antimicrobial compounds. In this study, the antimicrobial activity (inhibitory and cidal) of HybenX®, a novel dessicating agent, in comparison with commonly used sodium hypochlorite and chlorhexidine, against a collection of bacterial and yeast strains representative of the most common human pathogenic species was evaluated. The minimal inhibitory, bactericidal, and fungicidal concentrations (MIC, MBC, and MFC, respectively) of the three different antimicrobial agents were evaluated by broth microdilution assays, followed by subculturing of suitable dilutions. HybenX® was active against 26 reference strains representative of staphylococci, enterococci, Enterobacterales, Gram-negative nonfermenters, and yeasts, although at higher concentrations than sodium hypochlorite and chlorhexidine. HybenX® MICs were 0.39% for bacteria (with MBCs ranging between 0.39% and 0.78%), and 0.1–0.78% for yeasts (with MFCs ranging between 0.78% and 1.6%). HybenX® exhibited potent inhibitory and cidal activity at low concentrations against several bacterial and yeast pathogens. These findings suggest that HybenX® could be of interest for the treatment of parodontal and endodontic infections and also for bacterial and fungal infections of other mucous membranes and skin as an alternative to sodium hypochlorite and chlorhexidine.

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