22 results on '"Annette W. Fothergill"'
Search Results
2. Identification of a New Class of Antifungals Targeting the Synthesis of Fungal Sphingolipids
- Author
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Visesato Mor, Antonella Rella, Amir M. Farnoud, Ashutosh Singh, Mansa Munshi, Arielle Bryan, Shamoon Naseem, James B. Konopka, Iwao Ojima, Erika Bullesbach, Alan Ashbaugh, Michael J. Linke, Melanie Cushion, Margaret Collins, Hari Krishna Ananthula, Larry Sallans, Pankaj B. Desai, Nathan P. Wiederhold, Annette W. Fothergill, William R. Kirkpatrick, Thomas Patterson, Lai Hong Wong, Sunita Sinha, Guri Giaever, Corey Nislow, Patrick Flaherty, Xuewen Pan, Gabriele Vargas Cesar, Patricia de Melo Tavares, Susana Frases, Kildare Miranda, Marcio L. Rodrigues, Chiara Luberto, Leonardo Nimrichter, and Maurizio Del Poeta
- Subjects
Microbiology ,QR1-502 - Abstract
ABSTRACT Recent estimates suggest that >300 million people are afflicted by serious fungal infections worldwide. Current antifungal drugs are static and toxic and/or have a narrow spectrum of activity. Thus, there is an urgent need for the development of new antifungal drugs. The fungal sphingolipid glucosylceramide (GlcCer) is critical in promoting virulence of a variety of human-pathogenic fungi. In this study, we screened a synthetic drug library for compounds that target the synthesis of fungal, but not mammalian, GlcCer and found two compounds [N′-(3-bromo-4-hydroxybenzylidene)-2-methylbenzohydrazide (BHBM) and its derivative, 3-bromo-N′-(3-bromo-4-hydroxybenzylidene) benzohydrazide (D0)] that were highly effective in vitro and in vivo against several pathogenic fungi. BHBM and D0 were well tolerated in animals and are highly synergistic or additive to current antifungals. BHBM and D0 significantly affected fungal cell morphology and resulted in the accumulation of intracellular vesicles. Deep-sequencing analysis of drug-resistant mutants revealed that four protein products, encoded by genes APL5, COS111, MKK1, and STE2, which are involved in vesicular transport and cell cycle progression, are targeted by BHBM. IMPORTANCE Fungal infections are a significant cause of morbidity and mortality worldwide. Current antifungal drugs suffer from various drawbacks, including toxicity, drug resistance, and narrow spectrum of activity. In this study, we have demonstrated that pharmaceutical inhibition of fungal glucosylceramide presents a new opportunity to treat cryptococcosis and various other fungal infections. In addition to being effective against pathogenic fungi, the compounds discovered in this study were well tolerated by animals and additive to current antifungals. These findings suggest that these drugs might pave the way for the development of a new class of antifungals.
- Published
- 2015
- Full Text
- View/download PDF
3. The Celecoxib Derivative AR-12 Has Broad-Spectrum Antifungal Activity In Vitro and Improves the Activity of Fluconazole in a Murine Model of Cryptococcosis
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Melanie T. Cushion, Justin P. Halterman, Kristy Koselny, Thomas F. Patterson, Nathan P. Wiederhold, Annette W. Fothergill, Damian J. Krysan, Chad Rappelye, Louis DiDone, Melanie Wellington, and Julianne Green
- Subjects
Male ,0301 basic medicine ,Antifungal Agents ,030106 microbiology ,Drug Evaluation, Preclinical ,Mice, Inbred Strains ,Microbial Sensitivity Tests ,Saccharomyces cerevisiae ,Pharmacology ,Echinocandins ,Lipopeptides ,03 medical and health sciences ,chemistry.chemical_compound ,Caspofungin ,Drug Resistance, Fungal ,In vivo ,Gene Expression Regulation, Fungal ,Histoplasma ,medicine ,Animals ,Experimental Therapeutics ,Pharmacology (medical) ,Candida albicans ,Fluconazole ,Candida ,Cryptococcus neoformans ,chemistry.chemical_classification ,Sulfonamides ,biology ,Pneumocystis ,Drug Synergism ,Cryptococcosis ,medicine.disease ,biology.organism_classification ,Disease Models, Animal ,Infectious Diseases ,chemistry ,Celecoxib ,Pyrazoles ,Azole ,medicine.drug - Abstract
Only one new class of antifungal drugs has been introduced into clinical practice in the last 30 years, and thus the identification of small molecules with novel mechanisms of action is an important goal of current anti-infective research. Here, we describe the characterization of the spectrum of in vitro activity and in vivo activity of AR-12, a celecoxib derivative which has been tested in a phase I clinical trial as an anticancer agent. AR-12 inhibits fungal acetyl coenzyme A (acetyl-CoA) synthetase in vitro and is fungicidal at concentrations similar to those achieved in human plasma. AR-12 has a broad spectrum of activity, including activity against yeasts (e.g., Candida albicans , non- albicans Candida spp., Cryptococcus neoformans ), molds (e.g., Fusarium , Mucor ), and dimorphic fungi ( Blastomyces , Histoplasma , and Coccidioides ) with MICs of 2 to 4 μg/ml. AR-12 is also active against azole- and echinocandin-resistant Candida isolates, and subinhibitory AR-12 concentrations increase the susceptibility of fluconazole- and echinocandin-resistant Candida isolates. Finally, AR-12 also increases the activity of fluconazole in a murine model of cryptococcosis. Taken together, these data indicate that AR-12 represents a promising class of small molecules with broad-spectrum antifungal activity.
- Published
- 2016
4. The Investigational Fungal Cyp51 Inhibitor VT-1129 Demonstrates Potent In Vitro Activity against Cryptococcus neoformans and Cryptococcus gattii
- Author
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Shawn R. Lockhart, William J. Hoekstra, Annette W. Fothergill, Thomas F. Patterson, Carol B. Bolden, Naureen Iqbal, Nathan P. Wiederhold, Robert J. Schotzinger, Nina T. Grossman, Stephen Brand, Edward P. Garvey, and Elizabeth A. Ottinger
- Subjects
0301 basic medicine ,Antifungal Agents ,Genotype ,Pyridines ,030106 microbiology ,Gene Expression ,Tetrazoles ,Microbial Sensitivity Tests ,Drug resistance ,Microbiology ,Fungal Proteins ,Sterol 14-Demethylase ,03 medical and health sciences ,Drug Resistance, Fungal ,medicine ,Pharmacology (medical) ,Fluconazole ,Cryptococcus gattii ,Pharmacology ,Cryptococcus neoformans ,Fungal protein ,biology ,Fungal genetics ,Drugs, Investigational ,bacterial infections and mycoses ,biology.organism_classification ,In vitro ,030104 developmental biology ,Infectious Diseases ,Susceptibility ,14-alpha Demethylase Inhibitors ,medicine.drug - Abstract
The in vitro activities of the novel fungal Cyp51 inhibitor VT-1129 were evaluated against a large panel of Cryptococcus neoformans and Cryptococcus gattii isolates. VT-1129 demonstrated potent activities against both Cryptococcus species as demonstrated by low MIC 50 and MIC 90 values. For C. gattii , the in vitro potency was maintained against all genotypes. In addition, significantly lower geometric mean MICs were observed for VT-1129 than for fluconazole against C. neoformans , including isolates with reduced fluconazole susceptibility.
- Published
- 2016
5. Update from the Laboratory
- Author
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Deanna A. Sutton, Annette W. Fothergill, Mohammad T. Albataineh, and Nathan P. Wiederhold
- Subjects
0301 basic medicine ,Microbiology (medical) ,Antifungal ,Susceptibility testing ,Resistance (ecology) ,medicine.drug_class ,business.industry ,030106 microbiology ,Immunocompromised patient ,Bioinformatics ,Microbiology ,03 medical and health sciences ,Infectious Diseases ,Invasive Mycoses ,medicine ,Identification (biology) ,business - Abstract
Despite the availability of new diagnostic assays and broad-spectrum antifungal agents, invasive fungal infections remain a significant challenge to clinicians and are associated with marked morbidity and mortality. In addition, the number of etiologic agents of invasive mycoses has increased accompanied by an expansion in the immunocompromised patient populations, and the use of molecular tools for fungal identification and characterization has resulted in the discovery of several cryptic species. This article reviews various methods used to identify fungi and perform antifungal susceptibility testing in the clinical laboratory. Recent developments in antifungal resistance are also discussed.
- Published
- 2016
6. Multilaboratory Evaluation of In Vitro Antifungal Susceptibility Testing of Dermatophytes for ME1111
- Author
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Robert Rennie, Mahmoud A. Ghannoum, Luis Ostrosky-Zeichner, Daniel J. Diekema, Nathan P. Wiederhold, Vishnu Chaturvedi, Thomas J. Walsh, Nancy L. Wengenack, and Annette W. Fothergill
- Subjects
0301 basic medicine ,Microbiology (medical) ,Antifungal ,Susceptibility testing ,Antifungal Agents ,medicine.drug_class ,Epidermophyton floccosum ,030106 microbiology ,Mycology ,Microbial Sensitivity Tests ,Trichophyton rubrum ,Microbiology ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Phenols ,medicine ,Dermatomycoses ,Humans ,Trichophyton ,Reproducibility ,biology ,Arthrodermataceae ,Reproducibility of Results ,biology.organism_classification ,In vitro ,Pyrazoles - Abstract
ME1111 is a novel small molecule antifungal agent under development for the topical treatment of onychomycosis. Standardization of the susceptibility testing method for this candidate antifungal is needed. Toward this end, 8 independent laboratories determined the interlaboratory reproducibility of ME1111 susceptibility testing. In addition, we subsequently identified 2 strains as quality control (QC) isolates for the method. In the reproducibility study, 5 blinded clinical strains each of Trichophyton rubrum , Trichophyton mentagrophytes , and Epidermophyton floccosum were tested, while the QC study tested 6 blinded T. rubrum or T. mentagrophytes ATCC strains. Testing was performed in frozen microtiter panels according to the Clinical and Laboratory Standards Institute (CLSI) M38-A2 methodology. In the reproducibility study, 9 of 15 clinical strains showed interlaboratory agreement of >90% at the 80% inhibition endpoint, with a range of agreement of 76.2% to 100%. In the QC study, 4 of the 6 ATCC strains showed interlaboratory agreement of >90%. ME1111 demonstrated excellent interlaboratory agreement when tested against dermatophytes. Based on this data, the CLSI Subcommittee on Antifungal Susceptibility Tests approved the susceptibility testing of ME1111 against dermatophytes according to M38-A2 methodology, which stipulates RPMI 1640 as the test medium, an inoculum size of 1 to 3 × 10 3 CFU/ml, and an incubation time and temperature of 96 h at 35°C. The MIC endpoint should be 80% inhibition compared with the growth control. T. rubrum ATCC MYA-4438 and T. mentagrophytes ATCC 28185 were selected as QC isolates, with an acceptable range of 0.12 to 1 μg/ml for the two strains.
- Published
- 2016
7. Erratum for Mor et al., 'Identification of a New Class of Antifungals Targeting the Synthesis of Fungal Sphingolipids'
- Author
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Amir M. Farnoud, Hari Krishna Ananthula, Lai Hong Wong, Ashutosh Singh, Visesato Mor, Michael J. Linke, Margaret S. Collins, Susana Frases, Chiara Luberto, Gabriele Vargas Cesar, Xuewen Pan, Corey Nislow, Erika E. Büllesbach, William R. Kirkpatrick, Annette W. Fothergill, Larry Sallans, Alan Ashbaugh, Iwao Ojima, James B. Konopka, Melanie T. Cushion, Marcio L. Rodrigues, Thomas F. Patterson, Leonardo Nimrichter, Arielle M. Bryan, Maurizio Del Poeta, Shamoon Naseem, Patricia de Melo Tavares, Kildare Miranda, Antonella Rella, Sunita Sinha, Nathan P. Wiederhold, Patrick Flaherty, Pankaj B. Desai, Guri Giaever, and Mansa Munshi
- Subjects
0301 basic medicine ,Antifungal Agents ,Drug-Related Side Effects and Adverse Reactions ,Cell Survival ,030106 microbiology ,Colony Count, Microbial ,Drug Evaluation, Preclinical ,Microbial Sensitivity Tests ,Computational biology ,Biology ,Microbiology ,Cell Line ,Mice ,03 medical and health sciences ,Microscopy, Electron, Transmission ,Virology ,Benzyl Compounds ,Animals ,Sphingolipids ,Microbial Viability ,Molecular Structure ,Macrophages ,Candidiasis ,Fungi ,Drug Synergism ,Sphingolipid ,QR1-502 ,Biosynthetic Pathways ,Disease Models, Animal ,Treatment Outcome ,Identification (biology) ,Erratum ,Research Article - Abstract
Recent estimates suggest that >300 million people are afflicted by serious fungal infections worldwide. Current antifungal drugs are static and toxic and/or have a narrow spectrum of activity. Thus, there is an urgent need for the development of new antifungal drugs. The fungal sphingolipid glucosylceramide (GlcCer) is critical in promoting virulence of a variety of human-pathogenic fungi. In this study, we screened a synthetic drug library for compounds that target the synthesis of fungal, but not mammalian, GlcCer and found two compounds [N′-(3-bromo-4-hydroxybenzylidene)-2-methylbenzohydrazide (BHBM) and its derivative, 3-bromo-N′-(3-bromo-4-hydroxybenzylidene) benzohydrazide (D0)] that were highly effective in vitro and in vivo against several pathogenic fungi. BHBM and D0 were well tolerated in animals and are highly synergistic or additive to current antifungals. BHBM and D0 significantly affected fungal cell morphology and resulted in the accumulation of intracellular vesicles. Deep-sequencing analysis of drug-resistant mutants revealed that four protein products, encoded by genes APL5, COS111, MKK1, and STE2, which are involved in vesicular transport and cell cycle progression, are targeted by BHBM., IMPORTANCE Fungal infections are a significant cause of morbidity and mortality worldwide. Current antifungal drugs suffer from various drawbacks, including toxicity, drug resistance, and narrow spectrum of activity. In this study, we have demonstrated that pharmaceutical inhibition of fungal glucosylceramide presents a new opportunity to treat cryptococcosis and various other fungal infections. In addition to being effective against pathogenic fungi, the compounds discovered in this study were well tolerated by animals and additive to current antifungals. These findings suggest that these drugs might pave the way for the development of a new class of antifungals.
- Published
- 2018
8. VT-1161 Protects Immunosuppressed Mice from Rhizopus arrhizus var. arrhizus Infection
- Author
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Thomas F. Patterson, William J. Hoekstra, Edward P. Garvey, Robert J. Schotzinger, Scott G. Filler, Ashraf S. Ibrahim, Teclegiorgis Gebremariam, Annette W. Fothergill, and Nathan P. Wiederhold
- Subjects
Male ,Antifungal Agents ,Pyridines ,Rhizopus arrhizus var. arrhizus ,Tetrazoles ,Microbial Sensitivity Tests ,Biology ,Microbiology ,Drug levels ,Immunocompromised Host ,Mice ,Species Specificity ,Rhizopus ,Amphotericin B ,medicine ,Animals ,Mucormycosis ,Experimental Therapeutics ,Pharmacology (medical) ,Rhizopus arrhizus ,Pharmacology ,Mice, Inbred ICR ,medicine.disease ,biology.organism_classification ,Survival Analysis ,In vitro ,Infectious Diseases ,Liposomal amphotericin ,medicine.drug - Abstract
We studied the efficacy of the investigational drug VT-1161 against mucormycosis. VT-1161 had more potent in vitro activity against Rhizopus arrhizus var. arrhizus than against R. arrhizus var. delemar . VT-1161 treatment demonstrated dose-dependent plasma drug levels with prolonged survival time and lowered tissue fungal burden in immunosuppressed mice infected with R. arrhizus var. arrhizus and was as effective as high-dose liposomal amphotericin B treatment. These results support further development of VT-1161 against mucormycosis.
- Published
- 2015
9. The Novel Arylamidine T-2307 Maintains In Vitro and In Vivo Activity against Echinocandin-Resistant Candida albicans
- Author
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Thomas F. Patterson, Annette W. Fothergill, Laura K. Najvar, Marcos Olivo, Nathan P. Wiederhold, Dora I. McCarthy, Junichi Mitsuyama, Rosie Bocanegra, Yoshiko Fukuda, and William R. Kirkpatrick
- Subjects
Male ,Antifungal Agents ,Echinocandin ,Amidines ,Improved survival ,Microbial Sensitivity Tests ,Pharmacology ,Placebo ,Microbiology ,Echinocandins ,Mice ,chemistry.chemical_compound ,Drug Resistance, Fungal ,In vivo ,Candida albicans ,polycyclic compounds ,medicine ,Animals ,Experimental Therapeutics ,Pharmacology (medical) ,Mice, Inbred ICR ,biology ,Candidiasis ,bacterial infections and mycoses ,biology.organism_classification ,In vitro ,Corpus albicans ,Infectious Diseases ,chemistry ,Caspofungin ,medicine.drug - Abstract
We evaluated the in vitro and in vivo activities of the investigational arylamidine T-2307 against echinocandin-resistant Candida albicans . T-2307 demonstrated potent in vitro activity, and daily subcutaneous doses between 0.75 and 6 mg/kg of body weight significantly improved survival and reduced fungal burden compared to placebo control and caspofungin (10 mg/kg/day) in mice with invasive candidiasis caused by an echinocandin-resistant strain. Thus, T-2307 may have potential use in the treatment of echinocandin-resistant C. albicans infections.
- Published
- 2015
10. Repurposing auranofin as an antifungal: In vitro activity against a variety of medically important fungi
- Author
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Nathan P. Wiederhold, Annette W. Fothergill, Anand Srinivasan, Ashok K. Chaturvedi, Thomas F. Patterson, Jose L. Lopez-Ribot, Floyd L. Wormley, and Anand K. Ramasubramanian
- Subjects
0301 basic medicine ,Microbiology (medical) ,Antifungal ,Auranofin ,Antifungal Agents ,medicine.drug_class ,030106 microbiology ,Immunology ,Microbial Sensitivity Tests ,Pharmacology ,Biology ,Microbiology ,03 medical and health sciences ,Candida albicans ,medicine ,Humans ,Repurposing ,Aspergillus fumigatus ,Brief Report ,Candidiasis ,Drug Repositioning ,Fungi ,medicine.disease ,biology.organism_classification ,In vitro ,Antirheumatic Agents ,Drug repositioning ,030104 developmental biology ,Infectious Diseases ,Rheumatoid arthritis ,Parasitology ,medicine.drug - Abstract
Repositioning old drugs can significantly decrease the time and effort that it takes to develop novel antifungal therapeutics, which represents a pressing and unmet clinical need due to the devastating nature of fungal infections. We have previously described the activity of auranofin, a gold thiol compound used to treat rheumatoid arthritis, against Candida albicans biofilms. Here we evaluate its antifungal spectrum of action and describe its activity against a variety of medically important fungi.
- Published
- 2016
11. Effects of Treated versus Untreated Polystyrene on Caspofungin In Vitro Activity against Candida Species
- Author
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Annette W. Fothergill, Mohammad T. Albataineh, Nathan P. Wiederhold, Carmita Sanders, M. L. McElmeel, and Dora I. McCarthy
- Subjects
0301 basic medicine ,Microbiology (medical) ,Antifungal Agents ,030106 microbiology ,Mycology ,Microbial Sensitivity Tests ,Biology ,Microbiology ,03 medical and health sciences ,chemistry.chemical_compound ,Echinocandins ,Lipopeptides ,Caspofungin ,polycyclic compounds ,Humans ,Etest ,Candida ,Broth microdilution ,Reproducibility of Results ,biochemical phenomena, metabolism, and nutrition ,bacterial infections and mycoses ,In vitro ,Corpus albicans ,chemistry ,Polystyrenes - Abstract
Significant interlaboratory variability is observed in testing the caspofungin susceptibility of Candida species by both the CLSI and EUCAST broth microdilution methodologies. We evaluated the influence of treated versus untreated polystyrene microtiter trays on caspofungin MICs using 209 isolates of four Candida species, including 16 C. albicans and 11 C. glabrata isolates with defined FKS mutations. Caspofungin MICs were also determined using the commercially available YeastOne and Etest assays and 102 isolates. All C. glabrata isolates had caspofungin MICs of ≥0.5 μg/ml, the clinical breakpoint for caspofungin resistance in this species, measured using trays made of treated polystyrene, regardless of the FKS status. In contrast, susceptible isolates could readily be distinguished from resistant/non-wild-type isolates when caspofungin MICs were measured using untreated polystyrene trays and both the YeastOne and Etest assays. Similar results were also observed for C. krusei isolates, as all isolates had caspofungin MICs above the threshold for resistance measured using treated polystyrene trays. In contrast, C. albicans isolates could be correctly identified as susceptible or resistant when caspofungin MICs were measured with treated or untreated trays and with the YeastOne and Etest assays. MICs falsely elevated above the resistance breakpoint were also not observed for C. tropicalis isolates. These results demonstrated that the use of treated polystyrene may be one factor that leads to falsely elevated caspofungin in vitro susceptibility results and that this may also be a greater issue for some Candida species than for others.
- Published
- 2016
12. Update from the Laboratory: Clinical Identification and Susceptibility Testing of Fungi and Trends in Antifungal Resistance
- Author
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Mohammad T, Albataineh, Deanna A, Sutton, Annette W, Fothergill, and Nathan P, Wiederhold
- Subjects
Antifungal Agents ,Mycoses ,Drug Resistance, Fungal ,Fungi ,Humans ,Microbial Sensitivity Tests ,Laboratories - Abstract
Despite the availability of new diagnostic assays and broad-spectrum antifungal agents, invasive fungal infections remain a significant challenge to clinicians and are associated with marked morbidity and mortality. In addition, the number of etiologic agents of invasive mycoses has increased accompanied by an expansion in the immunocompromised patient populations, and the use of molecular tools for fungal identification and characterization has resulted in the discovery of several cryptic species. This article reviews various methods used to identify fungi and perform antifungal susceptibility testing in the clinical laboratory. Recent developments in antifungal resistance are also discussed.
- Published
- 2016
13. Voriconazole minimum inhibitory concentrations are predictive of treatment outcome in experimental murine infections by Candida glabrata
- Author
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Deanna A. Sutton, Marta Sanchis, Josep Guarro, Annette W. Fothergill, Javier Capilla, Adela Martin-Vicente, Nathan P. Wiederhold, Mariana Castanheira, Unitat de Micologia i Microbiologia Ambiental, Ciències Mèdiques Bàsiques, and Universitat Rovira i Virgili
- Subjects
Male ,0301 basic medicine ,Microbiology (medical) ,Antifungal Agents ,030106 microbiology ,Treatment outcome ,Colony Count, Microbial ,Candida glabrata ,Microbial Sensitivity Tests ,Pharmacology ,0924-8579 ,Kidney ,Inhibitory postsynaptic potential ,Mice ,03 medical and health sciences ,In vivo ,medicine ,voriconazole ,Animals ,Pharmacology (medical) ,Voriconazole ,Ciències de la salut ,biology ,fungal infection ,Candidiasis ,Health sciences ,General Medicine ,biology.organism_classification ,Ciencias de la salud ,Treatment efficacy ,In vitro ,Disease Models, Animal ,Treatment Outcome ,Infectious Diseases ,Càndida glabrata ,Murine model ,Micosi ,Immunology ,Voriconazol ,medicine.drug - Abstract
DOI: 10.1016/j.ijantimicag.2015.12.020 In this study, 27 clinical isolates of Candida glabrata with voriconazole (VRC) minimum inhibitory concentrations (MICs) ranging from ¿0.03 ¿g/mL to 8 ¿g/mL were tested to determine whether in vitro data are predictive of in vivo efficacy. The efficacy of VRC administered at 40 mg/kg was assayed in a neutropenic murine model of disseminated infection by C. glabrata. The reduction in fungal tissue burden in the kidneys was used as a marker of treatment efficacy. VRC reduced the fungal tissue burden in mice infected with strains that had MICs below the epidemiological cut-off value (ECV) of 0.25 ¿g/mL. Variable efficacy of VRC was obtained when the MIC equalled the ECV, and VRC was ineffective when the MIC exceeded the ECV. These results suggest that the use of in vitro data could be useful to predict the outcome for infections by this fungus.
- Published
- 2016
- Full Text
- View/download PDF
14. First Detection of TR34 L98H and TR46 Y121F T289A Cyp51 Mutations in Aspergillus fumigatus Isolates in the United States
- Author
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Jonathan Lindner, Carmita Sanders, Annette W. Fothergill, Felipe Gutierrez, Veronica Garcia Gil, Mohammad T. Albataineh, Nathan P. Wiederhold, Hongxin Fan, Deanna A. Sutton, and Dora I. McCarthy
- Subjects
0301 basic medicine ,Microbiology (medical) ,Azoles ,Antifungal Agents ,030106 microbiology ,Mutation, Missense ,Azole resistance ,Mycology ,Microbial Sensitivity Tests ,Aspergillosis ,Aspergillus fumigatus ,Microbiology ,03 medical and health sciences ,Sterol 14-Demethylase ,Drug Resistance, Fungal ,medicine ,Humans ,In patient ,chemistry.chemical_classification ,biology ,biology.organism_classification ,medicine.disease ,United States ,chemistry ,Azole - Abstract
Azole resistance in Aspergillus fumigatus is an increasing problem. The TR34 L98H and TR46 Y121F T289A mutations that can occur in patients without previous azole exposure have been reported in Europe, Asia, the Middle East, Africa, and Australia. Here, we report the detection of both the TR34 L98H and TR46 Y121F T289A mutations in confirmed A. fumigatus isolates collected in institutions in the United States. These mutations, other mutations known to cause azole resistance, and azole MICs are reported here.
- Published
- 2015
15. The novel arylamidine T-2307 demonstrates in vitro and in vivo activity against echinocandin-resistant Candida glabrata
- Author
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Annette W. Fothergill, Laura K. Najvar, Rosie Bocanegra, Thomas F. Patterson, Nathan P. Wiederhold, Dora I. McCarthy, Junichi Mitsuyama, Yoshiko Fukuda, and Marcos Olivo
- Subjects
0301 basic medicine ,Microbiology (medical) ,Male ,Antifungal Agents ,Echinocandin ,030106 microbiology ,Amidines ,Colony Count, Microbial ,Candida glabrata ,Microbial Sensitivity Tests ,Biology ,Neutropenia ,Kidney ,Microbiology ,03 medical and health sciences ,chemistry.chemical_compound ,In vivo ,polycyclic compounds ,medicine ,Animals ,Humans ,Pharmacology (medical) ,Original Research ,Pharmacology ,Mice, Inbred ICR ,Candidiasis ,bacterial infections and mycoses ,medicine.disease ,Caspofungin Acetate ,biology.organism_classification ,In vitro ,Disease Models, Animal ,Infectious Diseases ,Treatment Outcome ,chemistry ,Immunocompetence ,Caspofungin ,medicine.drug - Abstract
OBJECTIVES Candida species are major causes of invasive mycoses in immunocompetent and immunocompromised hosts. Treatment options are limited in the setting of antifungal resistance and increased rates of echinocandin-resistant Candida glabrata have been reported. The novel arylamidine T-2307 demonstrates potent in vitro antifungal activity against Candida species. Our objective was to evaluate the in vitro and in vivo activity of T-2307 against resistant C. glabrata. METHODS In vitro activity was determined against 42 clinical C. glabrata isolates, including 17 echinocandin-resistant strains. Neutropenic ICR mice were inoculated intravenously with an echinocandin-resistant C. glabrata isolate (T-2307; caspofungin MICs ≤0.008 and 0.5 mg/L, respectively). Therapy with vehicle control, T-2307 (0.75, 1.5, 3 or 6 mg/kg subcutaneously once daily) or caspofungin (1 or 10 mg/kg intraperitoneally once daily) began 1 day post-challenge. Kidneys were collected on day 8 and fungal burden was assessed by counting cfu. RESULTS T-2307 demonstrated potent in vitro activity against C. glabrata (geometric mean MIC 0.0135 mg/L), which was maintained against echinocandin-resistant isolates (geometric mean MIC 0.0083 mg/L). T-2307 also demonstrated in vivo efficacy in mice infected with echinocandin-resistant C. glabrata. Significant reductions in fungal burden were observed at each dosage level of T-2307 compared with control. Reductions in fungal burden were also observed with high-dose caspofungin. CONCLUSIONS T-2307 demonstrated potent in vitro activity against C. glabrata, including echinocandin-resistant isolates, which translated into in vivo efficacy against invasive candidiasis caused by an echinocandin-resistant C. glabrata strain. These results demonstrate the potential for T-2307 as therapy against echinocandin-resistant Candida.
- Published
- 2015
16. Identification of a New Class of Antifungals Targeting the Synthesis of Fungal Sphingolipids
- Author
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Sunita Sinha, Larry Sallans, Ashutosh Singh, Amir M. Farnoud, Shamoon Naseem, Pankaj B. Desai, Antonella Rella, Kildare Miranda, James B. Konopka, Guri Giaever, Iwao Ojima, Thomas F. Patterson, Margaret S. Collins, Nathan P. Wiederhold, Gabriele Vargas Cesar, Erika E. Büllesbach, Alan Ashbaugh, Hari Krishna Ananthula, Lai Hong Wong, Marcio L. Rodrigues, Arielle M. Bryan, Visesato Mor, William R. Kirkpatrick, Patricia de Melo Tavares, Michael J. Linke, Mansa Munshi, Maurizio Del Poeta, Xuewen Pan, Corey Nislow, Annette W. Fothergill, Susana Frases, Patrick Flaherty, Leonardo Nimrichter, Chiara Luberto, and Melanie T. Cushion
- Subjects
Virulence ,Drug resistance ,Pharmacology ,Biology ,medicine.disease ,Cell morphology ,Microbiology ,Sphingolipid ,QR1-502 ,In vitro ,3. Good health ,In vivo ,Cell culture ,Virology ,Cryptococcosis ,medicine - Abstract
Recent estimates suggest that >300 million people are afflicted by serious fungal infections worldwide. Current antifungal drugs are static and toxic and/or have a narrow spectrum of activity. Thus, there is an urgent need for the development of new antifungal drugs. The fungal sphingolipid glucosylceramide (GlcCer) is critical in promoting virulence of a variety of human-pathogenic fungi. In this study, we screened a synthetic drug library for compounds that target the synthesis of fungal, but not mammalian, GlcCer and found two compounds [ N ′-(3-bromo-4-hydroxybenzylidene)-2-methylbenzohydrazide (BHBM) and its derivative, 3-bromo- N ′-(3-bromo-4-hydroxybenzylidene) benzohydrazide (D0)] that were highly effective in vitro and in vivo against several pathogenic fungi. BHBM and D0 were well tolerated in animals and are highly synergistic or additive to current antifungals. BHBM and D0 significantly affected fungal cell morphology and resulted in the accumulation of intracellular vesicles. Deep-sequencing analysis of drug-resistant mutants revealed that four protein products, encoded by genes APL5 , COS111 , MKK1 , and STE2 , which are involved in vesicular transport and cell cycle progression, are targeted by BHBM. IMPORTANCE Fungal infections are a significant cause of morbidity and mortality worldwide. Current antifungal drugs suffer from various drawbacks, including toxicity, drug resistance, and narrow spectrum of activity. In this study, we have demonstrated that pharmaceutical inhibition of fungal glucosylceramide presents a new opportunity to treat cryptococcosis and various other fungal infections. In addition to being effective against pathogenic fungi, the compounds discovered in this study were well tolerated by animals and additive to current antifungals. These findings suggest that these drugs might pave the way for the development of a new class of antifungals.
- Published
- 2015
17. Detection of triazole resistance among Candida species by matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS)
- Author
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Nathan P. Wiederhold, Deanna A. Sutton, Annette W. Fothergill, and Mehmet Ali Saraçli
- Subjects
Voriconazole ,Posaconazole ,Reproducibility ,Antifungal Agents ,Triazole ,Reproducibility of Results ,General Medicine ,Microbial Sensitivity Tests ,Triazoles ,Corpus albicans ,Microbiology ,Matrix-assisted laser desorption/ionization ,chemistry.chemical_compound ,Infectious Diseases ,Antibiotic resistance ,chemistry ,Drug Resistance, Fungal ,Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ,medicine ,Humans ,Fluconazole ,medicine.drug ,Candida - Abstract
MALDI-TOF MS can rapidly identify microorganisms to the species level and may be able to detect antimicrobial resistance. We evaluated the ability of this technology to detect triazole resistance in Candida species.35 C. albicans, 35 C. glabrata, and 37 C. tropicalis strains were exposed to fluconazole, voriconazole, or posaconazole at two different concentrations plus a drug-free control: a midrange concentration (CLSI clinical breakpoint or epidemiologic cut-off value), and a high concentration (fluconazole 64 μg/ml, voriconazole & posaconazole 16 μg/ml). The MALDI-TOF MS spectra at these concentrations were used to create the individual composite correlation index (CCI) matrices for each isolate. When the CCI of the midrange/highest concentration was lower than that of the midrange/null concentration, the strain was classified as resistant. These results were then compared to the classifications for susceptible or resistant obtained by measuring the MICs according to the CLSI M27-A3 antifungal susceptibility testing (AFST) method.The MALDI-TOF MS assay was able to classify triazole susceptibility against all strains. Overall, essential agreement between MALDI-TOF MS and AFST varied between 54% and 97%, and was highest for posaconazole against C. glabrata. The reproducibility of the MALDI-TOF MS assay varied between 54.3 and 82.9% and was best for fluconazole against C. albicans and posaconazole against C. glabrata. Reproducibility was also higher for C. glabrata isolates compared to C. albicans and C. tropicalis.These results demonstrate that MALDI-TOF MS may be used to simultaneously determine the Candida species and classification as susceptible or resistant to triazole antifungals. Further studies are needed to refine the methodology and improve the reproducibility of this assay.
- Published
- 2015
18. Evaluation of VT-1161 for Treatment of Coccidioidomycosis in Murine Infection Models
- Author
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John N. Galgiani, Robert J. Schotzinger, Hien T. Trinh, Edward P. Garvey, William J. Hoekstra, Eric R. G. Lewis, Maria L. Lewis, Annette W. Fothergill, Bridget M. Barker, Adina Doyle, Lisa F. Shubitz, and Nathan P. Wiederhold
- Subjects
Antifungal Agents ,Pyridines ,Tetrazoles ,Microbial Sensitivity Tests ,Pharmacology ,Biology ,Placebo ,Fungal Proteins ,Mice ,Sterol 14-Demethylase ,Pharmacokinetics ,In vivo ,medicine ,Animals ,Humans ,Pharmacology (medical) ,Coccidioides ,Experimental Therapeutics ,Fluconazole ,Fungemia ,Fungal protein ,Coccidioidomycosis ,medicine.disease ,biology.organism_classification ,Survival Analysis ,Valley fever ,Disease Models, Animal ,Infectious Diseases ,Treatment Outcome ,14-alpha Demethylase Inhibitors ,Female ,medicine.drug ,Half-Life - Abstract
Coccidioidomycosis, or valley fever, is a growing health concern endemic to the southwestern United States. Safer, more effective, and more easily administered drugs are needed especially for severe, chronic, or unresponsive infections. The novel fungal CYP51 inhibitor VT-1161 demonstrated in vitro antifungal activity, with MIC 50 and MIC 90 values of 1 and 2 μg/ml, respectively, against 52 Coccidioides clinical isolates. In the initial animal study, oral doses of 10 and 50 mg/kg VT-1161 significantly reduced fungal burdens and increased survival time in a lethal respiratory model in comparison with treatment with a placebo ( P < 0.001). Oral doses of 25 and 50 mg/kg VT-1161 were similarly efficacious in the murine central nervous system (CNS) model compared to placebo treatment ( P < 0.001). All comparisons with the positive-control drug, fluconazole at 50 mg/kg per day, demonstrated either statistical equivalence or superiority of VT-1161. VT-1161 treatment also prevented dissemination of infection from the original inoculation site to a greater extent than fluconazole. Many of these in vivo results can be explained by the long half-life of VT-1161 leading to sustained high plasma levels. Thus, the efficacy and pharmacokinetics of VT-1161 are attractive characteristics for long-term treatment of this serious fungal infection.
- Published
- 2015
19. Voriconazole minimum inhibitory concentrations are predictive of treatment outcome in experimental murine infections by Candida glabrata
- Author
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Unitat de Micologia i Microbiologia Ambiental, Ciències Mèdiques Bàsiques, Universitat Rovira i Virgili, Javier Luque; Marta Sanchis; Mariana Castanheira; Adela Martin-Vicente; Deanna A. Sutton; Annette W. Fothergill; Nathan P. Wiederhold; Josep Guarro, Unitat de Micologia i Microbiologia Ambiental, Ciències Mèdiques Bàsiques, Universitat Rovira i Virgili, and Javier Luque; Marta Sanchis; Mariana Castanheira; Adela Martin-Vicente; Deanna A. Sutton; Annette W. Fothergill; Nathan P. Wiederhold; Josep Guarro
- Abstract
DOI: 10.1016/j.ijantimicag.2015.12.020, In this study, 27 clinical isolates of Candida glabrata with voriconazole (VRC) minimum inhibitory concentrations (MICs) ranging from ¿0.03 ¿g/mL to 8 ¿g/mL were tested to determine whether in vitro data are predictive of in vivo efficacy. The efficacy of VRC administered at 40 mg/kg was assayed in a neutropenic murine model of disseminated infection by C. glabrata. The reduction in fungal tissue burden in the kidneys was used as a marker of treatment efficacy. VRC reduced the fungal tissue burden in mice infected with strains that had MICs below the epidemiological cut-off value (ECV) of 0.25 ¿g/mL. Variable efficacy of VRC was obtained when the MIC equalled the ECV, and VRC was ineffective when the MIC exceeded the ECV. These results suggest that the use of in vitro data could be useful to predict the outcome for infections by this fungus.
- Published
- 2016
20. The investigational agent E1210 is effective in treatment of experimental invasive candidiasis caused by resistant Candida albicans
- Author
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Dora I. McCarthy, William R. Kirkpatrick, Annette W. Fothergill, Frederick Duncanson, Thomas F. Patterson, Michael Everson, Laura K. Najvar, Rosie Bocanegra, Marcos Olivo, and Nathan P. Wiederhold
- Subjects
Male ,Antifungal Agents ,Aminopyridines ,Drug resistance ,Microbial Sensitivity Tests ,Pharmacology ,Microbiology ,chemistry.chemical_compound ,Echinocandins ,Lipopeptides ,Mice ,In vivo ,Caspofungin ,Drug Resistance, Fungal ,Candida albicans ,medicine ,polycyclic compounds ,Animals ,Pharmacology (medical) ,Candidiasis, Invasive ,Experimental Therapeutics ,Fluconazole ,Mice, Inbred ICR ,biology ,Dose-Response Relationship, Drug ,Isoxazoles ,biology.organism_classification ,bacterial infections and mycoses ,Corpus albicans ,Dose–response relationship ,Infectious Diseases ,chemistry ,Acyltransferase ,medicine.drug - Abstract
The in vitro and in vivo activity of the inositol acyltransferase inhibitor E1210 was evaluated against echinocandin-resistant Candida albicans . E1210 demonstrated potent in vitro activity, and in mice with invasive candidiasis caused by echinocandin-resistant C. albicans , oral doses of 10 and 40 mg E1210/kg of body weight twice daily significantly improved survival and reduced fungal burden compared to those of controls and mice treated with caspofungin (10 mg/kg/day). These results demonstrate the potential use of E1210 against resistant C. albicans infections.
- Published
- 2014
21. Experimental Therapy with Azoles against Candida guilliermondii
- Author
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Annette W. Fothergill, Marta Sanchis, Deanna A. Sutton, Francisco Javier Pastor, Javier Capilla, and Josep Guarro
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Pharmacology ,Voriconazole ,Azoles ,Posaconazole ,Antifungal Agents ,endocrine system diseases ,business.industry ,digestive, oral, and skin physiology ,Microbial Sensitivity Tests ,Triazoles ,Disseminated Candidiasis ,digestive system ,digestive system diseases ,Microbiology ,Infectious Diseases ,Murine model ,Experimental therapy ,medicine ,Pharmacology (medical) ,Experimental Therapeutics ,Candida guilliermondii ,business ,medicine.drug ,Candida - Abstract
We evaluated the in vitro killing activity of voriconazole (VRC) and posaconazole (PSC) against two clinical isolates of Candida guilliermondii . The two drugs showed fungistatic activity against both isolates and were effective in reducing kidney fungal burden in a neutropenic murine model of disseminated candidiasis in infected mice. PSC was significantly more effective than VRC against one of the strains. The serum levels of PSC and VRC were above the corresponding MICs for these isolates.
- Published
- 2014
22. Reply to Ma et al.: Osteomyelitis caused by Aspergillus species
- Author
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Lucia Brescini, E. Marchionni, Annette W. Fothergill, Pamela Castelli, Silvia Staffolani, Rosaria Gesuita, E. Gabrielli, Deanna A. Sutton, Francesco Barchiesi, and Elena Orsetti
- Subjects
Microbiology (medical) ,Aspergillus species ,Infectious Diseases ,Osteomyelitis ,medicine ,General Medicine ,Biology ,medicine.disease ,Humanities ,Microbiology - Abstract
E. Gabrielli, A. W. Fothergill, L. Brescini, D. A. Sutton, E. Marchionni, E. Orsetti , S. Staffolani, P. Castelli , R. Gesuita and F. Barchiesi 1) Clinica Malattie Infettive, Universit a Politecnica delle Marche, Ancona, 2) Fungus Testing Laboratory, University of Texas Health Science Center, San Antonio, Texas and 3) Centro di Epidemiologia, Biostatistica e Informatica Medica, Universit a Politecnica delle Marche, Ancona, Italy
- Published
- 2014
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