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Stylianou, Marios
Publications (10 of 11) Show all publications
Lopes, J. P., Stylianou, M., Backman, E., Holmberg, S., Ekoff, M., Nilsson, G. & Urban, C. F. (2019). Cryptococcus neoformans Induces MCP-1 Release and Delays the Death of Human Mast Cells. Frontiers in Cellular and Infection Microbiology, 9, Article ID 289.
Open this publication in new window or tab >>Cryptococcus neoformans Induces MCP-1 Release and Delays the Death of Human Mast Cells
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2019 (English)In: Frontiers in Cellular and Infection Microbiology, E-ISSN 2235-2988, Vol. 9, article id 289Article in journal (Refereed) Published
Abstract [en]

Cryptococcosis, caused by the basidiomycete Cryptococcus neoformans, is a life-threatening disease affecting approximately one million people per year worldwide. Infection can occur when C. neoformans cells are inhaled by immunocompromised people. In order to establish infection, the yeast must bypass recognition and clearance by immune cells guarding the tissue. Using in vitro infections, we characterized the role of mast cells (MCs) in cryptococcosis. We found that MCs recognize C. neoformans and release inflammatory mediators such as tryptase and cytokines. From the latter group MCs released mainly CCL-2/MCP-1, a strong chemoattractant for monocytic cells. We demonstrated that supernatants of infected MCs recruit monocytes but not neutrophils. During infection with C. neoformans, MCs have a limited ability to kill the yeast depending on the serotype. C. neoformans, in turn, modulates the lifespan of MCs both, by presence of its polysaccharide capsule and by secreting soluble modulators. Taken together, MCs might have important contributions to fungal clearance during early stages of cryptocococis where these cells regulate recruitment of monocytes to mucosal tissues.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2019
Keywords
innate immunity, Cryptococcus neoformans, mast cells, monocytes, monocyte chemoattractant protein 1/CCL-2, fungi
National Category
Immunology in the medical area Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-162849 (URN)10.3389/fcimb.2019.00289 (DOI)000480550400001 ()31456952 (PubMedID)
Available from: 2019-09-06 Created: 2019-09-06 Last updated: 2019-09-06Bibliographically approved
Hosseinzadeh, A., Stylianou, M., Lopes, J. P., Müller, D. C., Häggman, A., Holmberg, S., . . . Urban, C. F. (2019). Stable Redox-Cycling Nitroxide Tempol has Antifungal and Immune-modulatory Properties. Frontiers in Microbiology, 10, Article ID 1843.
Open this publication in new window or tab >>Stable Redox-Cycling Nitroxide Tempol has Antifungal and Immune-modulatory Properties
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2019 (English)In: Frontiers in Microbiology, ISSN 1664-302X, E-ISSN 1664-302X, Vol. 10, article id 1843Article in journal (Refereed) Published
Abstract [en]

Invasive mycoses remain underdiagnosed and difficult to treat. Hospitalized individuals with compromised immunity increase in number and constitute the main risk group for severe fungal infections. Current antifungal therapy is hampered by slow and insensitive diagnostics and frequent toxic side effects of standard antifungal drugs. Identification of new antifungal compounds with high efficacy and low toxicity is therefore urgently required. We investigated the antifungal activity of tempol, a cell-permeable nitroxide. To narrow down possible mode of action we used RNA-seq technology and metabolomics to probe for pathways specifically disrupted in the human fungal pathogen Candida albicans due to tempol administration. We found genes upregulated which are involved in iron homeostasis, mitochondrial stress, steroid synthesis, and amino acid metabolism. In an ex vivo whole blood infection, tempol treatment reduced C. albicans colony forming units and at the same time increased the release of pro-inflammatory cytokines, such as interleukin 8 (IL-8, monocyte chemoattractant protein-1, and macrophage migration inhibitory factor). In a systemic mouse model, tempol was partially protective with a significant reduction of fungal burden in the kidneys of infected animals during infection onset. The results obtained propose tempol as a promising new antifungal compound and open new opportunities for the future development of novel therapies.

Keywords
antifungal activity, redox active, immunomodulators, candidiasis, Candida albicans, Candida glabrata
National Category
Microbiology in the medical area
Research subject
Infectious Diseases
Identifiers
urn:nbn:se:umu:diva-151596 (URN)10.3389/fmicb.2019.01843 (DOI)000481763300001 ()31481939 (PubMedID)
Funder
Swedish Research Council, 2014-02281The Kempe Foundations, 1453
Note

Originally included in thesis in manuscript form 

Available from: 2018-09-07 Created: 2018-09-07 Last updated: 2019-10-11Bibliographically approved
Thunström Salzer, A., Niemiec, M. J., Hosseinzadeh, A., Stylianou, M., Åstrom, F., Röhm, M., . . . Urban, C. F. (2018). Assessment of Neutrophil Chemotaxis Upon G-CSF Treatment of Healthy Stem Cell Donors and in Allogeneic Transplant Recipients. Frontiers in Immunology, 9, Article ID 1968.
Open this publication in new window or tab >>Assessment of Neutrophil Chemotaxis Upon G-CSF Treatment of Healthy Stem Cell Donors and in Allogeneic Transplant Recipients
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2018 (English)In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 9, article id 1968Article in journal (Refereed) Published
Abstract [en]

Neutrophils are crucial for the human innate immunity and constitute the majority of leukocytes in circulation. Thus, blood neutrophil counts serve as a measure for the immune system's functionality. Hematological patients often have low neutrophil counts due to disease or chemotherapy. To increase neutrophil counts and thereby preventing infections in high-risk patients, recombinant G-CSF is widely used as adjunct therapy to stimulate the maturation of neutrophils. In addition, G-CSF is utilized to recruit stem cells (SCs) into the peripheral blood of SC donors. Still, the actual functionality of neutrophils resulting from G-CSF treatment remains insufficiently understood. We tested the ex vivo functionality of neutrophils isolated from blood of G-CSF-treated healthy SC donors. We quantified chemotaxis, oxidative burst, and phagocytosis before and after treatment and detected significantly reduced chemotactic activity upon G-CSF treatment. Similarly, in vitro treatment of previously untreated neutrophils with G-CSF led to reduced chemotactic activity. In addition, we revealed that this effect persists in the allogeneic SC recipients up to 4 weeks after neutrophil engraftment. Our data indicates that neutrophil quantity, as a sole measure of immunocompetence in high-risk patients should be considered cautiously as neutrophil functionality might be affected by the primary treatment.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2018
Keywords
neutrophil, granulocyte colony stimulating factor (G-CSF), allogeneic transplant, chemotaxis, hematopoietic stern cell donor
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:umu:diva-152255 (URN)10.3389/fimmu.2018.01968 (DOI)000444324800001 ()30254629 (PubMedID)
Funder
Västerbotten County Council
Available from: 2018-10-03 Created: 2018-10-03 Last updated: 2018-10-03Bibliographically approved
Delgado, C., Florez, L., Lollett, I., Lopez, C., Kangeyan, S., Kumari, H., . . . Mathee, K. (2018). Pseudomonas aeruginosa Regulated Intramembrane Proteolysis: Protease MucP Can Overcome Mutations in the AlgO Periplasmic Protease To Restore Alginate Production in Nonmucoid Revertants. Journal of Bacteriology, 200(16), Article ID e00215-18.
Open this publication in new window or tab >>Pseudomonas aeruginosa Regulated Intramembrane Proteolysis: Protease MucP Can Overcome Mutations in the AlgO Periplasmic Protease To Restore Alginate Production in Nonmucoid Revertants
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2018 (English)In: Journal of Bacteriology, ISSN 0021-9193, E-ISSN 1098-5530, Vol. 200, no 16, article id e00215-18Article in journal (Refereed) Published
Abstract [en]

The progression of cystic fibrosis (CF) from an acute to a chronic disease is often associated with the conversion of the opportunistic pathogen Pseudomonas aeruginosa from a nonmucoid form to a mucoid form in the lung. This conversion involves the constitutive synthesis of the exopolysaccharide alginate, whose production is under the control of the AlgT/U sigma factor. This factor is regulated posttranslationally by an extremely unstable process and has been commonly attributed to mutations in the algT (algU) gene. By exploiting this unstable phenotype, we isolated 34 spontaneous nonmucoid variants arising from the mucoid strain PDO300, a PAO1 derivative containing the mucA22 allele commonly found in mucoid CF isolates. Complementation analysis using a minimal tiling path cosmid library revealed that most of these mutants mapped to two protease-encoding genes, algO, also known as prc or PA3257, and mucP. Interestingly, our algO mutations were complemented by both mucP and algO, leading us to delete, clone, and overexpress mucP, algO, mucE, and mucD in both wild-type PAO1 and PDO300 backgrounds to better understand the regulation of this complex regulatory mechanism. Our findings suggest that the regulatory proteases follow two pathways for regulated intramembrane proteolysis (RIP), where both the AlgO/MucP pathway and MucE/AlgW pathway are required in the wild-type strain but where the AlgO/MucP pathway can bypass the MucE/AlgW pathway in mucoid strains with membrane-associated forms of MucA with shortened C termini, such as the MucA22 variant. This work gives us a better understanding of how alginate production is regulated in the clinically important mucoid variants of Pseudomonas aeruginosa. IMPORTANCE Infection by the opportunistic pathogen Pseudomonas aeruginosa is the leading cause of morbidity and mortality seen in CF patients. Poor patient prognosis correlates with the genotypic and phenotypic change of the bacteria from a typical nonmucoid to a mucoid form in the CF lung, characterized by the overproduction of alginate. The expression of this exopolysaccharide is under the control an alternate sigma factor, AlgT/U, that is regulated posttranslationally by a series of proteases. A better understanding of this regulatory phenomenon will help in the development of therapies targeting alginate production, ultimately leading to an increase in the length and quality of life for those suffering from CF.

Place, publisher, year, edition, pages
American Society for Microbiology, 2018
Keywords
mucoid conversion, Prc/AlgO/Tsp, RseP/MucP/YaeL, sigma(E), sigma(22), AlgT/U, cystic fibrosis, sigma factors, sigma-22, sigma-E, anti-sigma factor
National Category
Microbiology
Identifiers
urn:nbn:se:umu:diva-150648 (URN)10.1128/JB.00215-18 (DOI)000439777600009 ()29784885 (PubMedID)2-s2.0-85050477965 (Scopus ID)
Available from: 2018-08-29 Created: 2018-08-29 Last updated: 2018-08-29Bibliographically approved
Bjornsdottir, H., Rudin, A. D., Klose, F. P., Elmwall, J., Welin, A., Stylianou, M., . . . Bylund, J. (2017). Phenol-soluble Modulin α Peptide Toxins from aggressive Staphylococcus aureus induce rapid Formation of neutrophil extracellular Traps through a reactive Oxygen species-independent Pathway. Frontiers in Immunology, 8, Article ID 257.
Open this publication in new window or tab >>Phenol-soluble Modulin α Peptide Toxins from aggressive Staphylococcus aureus induce rapid Formation of neutrophil extracellular Traps through a reactive Oxygen species-independent Pathway
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2017 (English)In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 8, article id 257Article in journal (Refereed) Published
Abstract [en]

Neutrophils have the ability to capture and kill microbes extracellularly through the formation of neutrophil extracellular traps (NETs). These are DNA and protein structures that neutrophils release extracellularly and are believed to function as a defense mechanism against microbes. The classic NET formation process, triggered by, e.g., bacteria, fungi, or by direct stimulation of protein kinase C through phorbol myristate acetate, is an active process that takes several hours and relies on the production of reactive oxygen species (ROS) that are further modified by myeloperoxidase (MPO). We show here that NET-like structures can also be formed by neutrophils after interaction with phenol-soluble modulin alpha (PSM alpha) that are cytotoxic membrane-disturbing peptides, secreted from community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA). The PSMa-induced NETs contained the typical protein markers and were able to capture microbes. The PSMa-induced NET structures were disintegrated upon prolonged exposure to DNase-positive S. aureus but not on exposure to DNase-negative Candida albicans. Opposed to classic NETosis, PSMa-triggered NET formation occurred very rapidly, independently of ROS or MPO, and was also manifest at 4 degrees C. These data indicate that rapid NETs release may result from cytotoxic membrane disturbance by PSMa peptides, a process that may be of importance for CA-MRSA virulence.

Keywords
community-acquired methicillin-resistant Staphylococcus aureus, PSM, NETs, ROS, FPR2, MPO, utrophil elastase, Papillon-Lefevre syndrome
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-133767 (URN)10.3389/fimmu.2017.00257 (DOI)000395693300001 ()28337204 (PubMedID)
Available from: 2017-05-03 Created: 2017-05-03 Last updated: 2018-06-09Bibliographically approved
Klein, O., Ngo-Nyekel, F., Stefanache, T., Torres, R., Salomonsson, M., Hallgren, J., . . . Maurer, M. (2016). Identification of Biological and Pharmaceutical Mast Cell- and Basophil-Related Targets [Letter to the editor]. Scandinavian Journal of Immunology, 83(6), 465-472
Open this publication in new window or tab >>Identification of Biological and Pharmaceutical Mast Cell- and Basophil-Related Targets
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2016 (English)In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 83, no 6, p. 465-472Article in journal, Letter (Refereed) Published
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-124522 (URN)10.1111/sji.12436 (DOI)000379922400009 ()27028428 (PubMedID)
Available from: 2016-08-24 Created: 2016-08-15 Last updated: 2018-06-07Bibliographically approved
Stylianou, M., Uvell, H., Lopes, J. P., Enquist, P.-A., Elofsson, M. & Urban, C. F. (2015). Novel High-Throughput Screening Method for Identification of Fungal Dimorphism Blockers. Journal of Biomolecular Screening, 20(2), 285-91
Open this publication in new window or tab >>Novel High-Throughput Screening Method for Identification of Fungal Dimorphism Blockers
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2015 (English)In: Journal of Biomolecular Screening, ISSN 1087-0571, E-ISSN 1552-454X, Vol. 20, no 2, p. 285-91Article in journal (Refereed) Published
Abstract [en]

Invasive mycoses have been increasing worldwide, with Candida spp. being the most prevalent fungal pathogen causing high morbidity and mortality in immunocompromised individuals. Only few antimycotics exist, often with severe side effects. Therefore, new antifungal drugs are urgently needed. Because the identification of antifungal compounds depends on fast and reliable assays, we present a new approach based on high-throughput image analysis to define cell morphology. Candida albicans and other fungi of the Candida clade switch between different growth morphologies, from budding yeast to filamentous hyphae. Yeasts are considered proliferative, whereas hyphae are required for invasion and dissemination. Thus, morphotype switching in many Candida spp. is connected to virulence and pathogenesis. It is, consequently, reasonable to presume that morphotype blockers interfere with the virulence, thereby preventing hazardous colonization. Our method efficiently differentiates yeast from hyphal cells using a combination of automated microscopy and image analysis. We selected the parameters length/width ratio and mean object shape to quantitatively discriminate yeasts and hyphae. Notably, Z' factor calculations for these parameters confirmed the suitability of our method for high-throughput screening. As a second stage, we determined cell viability to discriminate morphotype-switching inhibitors from those that are fungicidal. Thus, our method serves as a basis for the identification of candidates for next-generation antimycotics.

National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-101194 (URN)10.1177/1087057114552954 (DOI)000348642300012 ()25281739 (PubMedID)
Available from: 2015-03-24 Created: 2015-03-24 Last updated: 2018-08-01Bibliographically approved
Lopes, J. P., Stylianou, M., Nilsson, G. & Urban, C. F. (2015). Opportunistic pathogen Candida albicans elicits a temporal response in primary human mast cells. Scientific Reports, 5, Article ID 12287.
Open this publication in new window or tab >>Opportunistic pathogen Candida albicans elicits a temporal response in primary human mast cells
2015 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, article id 12287Article in journal (Refereed) Published
Abstract [en]

Immunosuppressed patients are frequently afflicted with severe mycoses caused by opportunistic fungal pathogens. Besides being a commensal, colonizing predominantly skin and mucosal surfaces, Candida albicans is the most common human fungal pathogen. Mast cells are present in tissues prone to fungal colonization being expectedly among the first immune cells to get into contact with C. albicans. However, mast cell-fungus interaction remains a neglected area of study. Here we show that human mast cells mounted specific responses towards C. albicans. Collectively, mast cell responses included the launch of initial, intermediate and late phase components determined by the secretion of granular proteins and cytokines. Initially mast cells reduced fungal viability and occasionally internalized yeasts. C. albicans could evade ingestion by intracellular growth leading to cellular death. Furthermore, secreted factors in the supernatants of infected cells recruited neutrophils, but not monocytes. Late stages were marked by the release of cytokines that are known to be anti-inflammatory suggesting a modulation of initial responses. C. albicans-infected mast cells formed extracellular DNA traps, which ensnared but did not kill the fungus. Our results suggest that mast cells serve as tissue sentinels modulating antifungal immune responses during C. albicans infection. Consequently, these findings open new doors for understanding fungal pathogenicity.

Place, publisher, year, edition, pages
Nature Publishing Group, 2015
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-106777 (URN)10.1038/srep12287 (DOI)000358152500001 ()26192381 (PubMedID)
Available from: 2015-08-20 Created: 2015-08-07 Last updated: 2018-09-07Bibliographically approved
Stylianou, M. (2015). Pharmaceutical And Immunollogical Challenge Of Fungal Pathogens. (Doctoral dissertation). Umeå Universitet
Open this publication in new window or tab >>Pharmaceutical And Immunollogical Challenge Of Fungal Pathogens
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Incidences of fungal infections are on the rise in immunosuppressed people. Predominant causative agents for these mycoses are species of the genus Candida, including Candida albicans, Candida glabrata and Candida dublieniensis. Despite a wide range of emerging pathogens, C. albicans remains the leading cause. According to recent epidemiological studies, blood stream infections with C. albicans cause annually ~55% mortality in approximately 300,000 patients from intensive care units worldwide. Furthermore, the percentage of morbidity linked to oral, esophageal and vulvovaginal mycoses cause by C. albicans reach up to 90%. Reasons for these medical concerns are the lack of efficient diagnostics and antifungal therapy.

Here, we therefore sought to find novel antifungal strategies inspired by innate immune cells, such as neutrophils. These phagocytes are able to block the fungal pathogenicity. Neutrophils are bloodstream leukocytes serving as the first line of defense against pathogenic microbes. It has been shown that neutrophils have a strong antifungal activity by impairing the conversion of the dimorphic C. albicans from yeast to hyphal form (Y-H). Consequently, we raised the question whether other immune cells, such as mast cells, with less phagocytic cabapilities may have similar activity to neutrophils.

Mast cells are tissue-dwelling cells. Mucosal tissue is rich in mast cells and usually constitutes the entry ports for fungal pathogens into the human body. A contribution of mast cells in antifungal defense is, thus, very likely. We human explored mast cell functions upon encounter with fungal pathogens. Interestingly, human mast cells show a transient potential to impair fungal viability. To understand the mechanism behind this impairment we analyzed the human mast cell functions in more detail. We found that human mast cells challenged with C. albicans, immediately degranulate and secrete distinct cytokines and chemokines in an orchestrated manner. The chemokines secreted attract neutrophils. Mast cells moreover are able to internalize fungal cells and to ‘commit suicide’ by releasing extracellular DNA traps that ensnare the pathogen.

 

The effectiveness of future antifungals is depended on targeting the pathogen virulence with more efficiency.

The dimorphism of C. albicans is proven to be essential its virulence. Blockage of this switching ability could render the pathogen avirulent. Consequently, we screened for compounds that mimic the neutrophils anti-dimorphic activity by screening small chemical molecule libraries that block Y-H transition. The screening of big chemical libraries requires a reliable, reproducible and rapid high-throughput screening assay (HTS). We developed an HTS assay based on automated microscopy and image analysis, thereby allowing to distinguish between yeast and filamentous forms. In order to find the ideal Y-H blocker, we also evaluated the cell viability via the count of ATP levels when challenged with the respective small chemical molecules.

 

Drug development is an elaborate and expensive process. We therefore applied our screening setup to identify antidimorphic/antifungal activity in compounds from two different chemical libraries including FDA-approved drugs. The study disclosed 7 off-patent antifungal drugs that have potent antimycotic activity, including 4 neoplastic agents, 2 antipsychotic drugs and 1 antianemic medication.

In a nutshell, we aimed to mimic the anti-dimorphic/antifungal activity of neutrophils with small chemical molecules. Furthermore, we elucidated how immune cells contribute to antifungal defense to exploit these mechanisms for the development of novel antifungal therapies. Thus, this thesis provides novel tools for the discovery of more efficient compounds, identifies previously unknown antifungal aspect of off-patent FDA-approved drugs and highlights the interplay of mast cells with pathogenic fungi with the aim to define new screening strategies.

Place, publisher, year, edition, pages
Umeå Universitet, 2015. p. 52
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1735
Keywords
mast cells, Candida albicans, yeast to hyphal form, antifungal drugs, repurposed drugs, HTS
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-107713 (URN)978-91-7601-308-3 (ISBN)
Public defence
2015-09-25, sal Eo4, byggnad 6E, NUS, Norrlands universitetssjukhus, Umeå, 10:00 (English)
Opponent
Supervisors
Available from: 2015-09-04 Created: 2015-08-27 Last updated: 2018-06-07Bibliographically approved
Stylianou, M., Kulesskiy, E., Lopes, J. P., Granlund, M., Wennerberg, K. & Urban, C. F. (2014). Antifungal Application of Nonantifungal Drugs. Antimicrobial Agents and Chemotherapy, 58(2), 1055-1062
Open this publication in new window or tab >>Antifungal Application of Nonantifungal Drugs
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2014 (English)In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 58, no 2, p. 1055-1062Article in journal (Refereed) Published
Abstract [en]

Candida species are the cause of 60% of all mycoses in immunosuppressed individuals, leading to similar to 150,000 deaths annually due to systemic infections, whereas the current antifungal therapies either have toxic side effects or are insufficiently efficient. We performed a screening of two compound libraries, the Enzo and the Institute for Molecular Medicine Finland (FIMM) oncology collection library, for anti-Candida activity based on the European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines. From a total of 844 drugs, 26 agents showed activity against Candida albicans. Of those, 12 were standard antifungal drugs (SADs) and 7 were off-target drugs previously reported to be active against Candida spp. The remaining 7 off-target drugs, amonafide, tosedostat, megestrol acetate, melengestrol acetate, stanozolol, trifluperidol, and haloperidol, were identified with this screen. The anti-Candida activities of the new agents were investigated by three individual assays using optical density, ATP levels, and microscopy. The antifungal activities of these drugs were comparable to those of the SADs found in the screen. The aminopeptidase inhibitor tosedostat, which is currently in a clinical trial phase for anticancer therapy, displayed a broad antifungal activity against different Candida spp., including Candida glabrata. Thus, this screen reveals agents that were previously unknown to be anti-Candida agents, which allows for the design of novel therapies against invasive candidiasis.

National Category
Microbiology
Identifiers
urn:nbn:se:umu:diva-86824 (URN)10.1128/AAC.01087-13 (DOI)000330637500053 ()
Available from: 2014-03-17 Created: 2014-03-11 Last updated: 2018-09-12Bibliographically approved
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