scholarly journals Antifungal Activities of SCY-078 (MK-3118) and Standard Antifungal Agents against Clinical Non-Aspergillus Mold Isolates

2015 ◽  
Vol 59 (7) ◽  
pp. 4308-4311 ◽  
Author(s):  
Frédéric Lamoth ◽  
Barbara D. Alexander
Keyword(s):  
Antifungal Agents ◽  
Antifungal Drugs ◽  
Paecilomyces Variotii ◽  
Glucan Synthase ◽  
Content Type ◽  
Antifungal Activities ◽  
Highly Active ◽  
Scedosporium Prolificans ◽  
Synthase Inhibitor

ABSTRACTThe limited armamentarium of active and oral antifungal drugs against emerging non-Aspergillusmolds is of particular concern. Current antifungal agents and the new orally available beta-1,3-d-glucan synthase inhibitor SCY-078 were testedin vitroagainst 135 clinical non-Aspergillusmold isolates. Akin to echinocandins, SCY-078 showed no or poor activity againstMucoromycotinaandFusariumspp. However, SCY-078 was highly active againstPaecilomyces variotiiand was the only compound displaying some activity against notoriously panresistantScedosporium prolificans.

scholarly journals Acylhydrazones as Antifungal Agents Targeting the Synthesis of Fungal Sphingolipids

2018 ◽  
Vol 62 (5) ◽  
Author(s):  
Cristina Lazzarini ◽  
Krupanandan Haranahalli ◽  
Robert Rieger ◽  
Hari Krishna Ananthula ◽  
Pankaj B. Desai ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Antifungal Drugs ◽  
Fungal Resistance ◽  
Content Type ◽  
Highly Active ◽  
Pharmacokinetic Properties ◽  
Pass Through

ABSTRACTThe incidence of invasive fungal infections has risen dramatically in recent decades. Current antifungal drugs are either toxic, likely to interact with other drugs, have a narrow spectrum of activity, or induce fungal resistance. Hence, there is a great need for new antifungals, possibly with novel mechanisms of action. Previously our group reported an acylhydrazone called BHBM that targeted the sphingolipid pathway and showed strong antifungal activity against several fungi. In this study, we screened 19 derivatives of BHBM. Three out of 19 derivatives were highly active againstCryptococcus neoformansin vitroand had low toxicity in mammalian cells. In particular, one of them, called D13, had a high selectivity index and showed better activity in an animal model of cryptococcosis, candidiasis, and pulmonary aspergillosis. D13 also displayed suitable pharmacokinetic properties and was able to pass through the blood-brain barrier. These results suggest that acylhydrazones are promising molecules for the research and development of new antifungal agents.

scholarly journals Differential Activity of the Oral Glucan Synthase Inhibitor SCY-078 against Wild-Type and Echinocandin-Resistant Strains of Candida Species

2017 ◽  
Vol 61 (8) ◽  
Author(s):  
Michael A. Pfaller ◽  
Shawn A. Messer ◽  
Paul R. Rhomberg ◽  
Katyna Borroto-Esoda ◽  
Mariana Castanheira
Keyword(s):  
Antifungal Agents ◽  
Wild Type ◽  
Active Inhibitor ◽  
Glucan Synthase ◽  
Content Type ◽  
Upper Limit ◽  
Resistant Strains ◽  
Synthase Inhibitor ◽  
Orally Active

ABSTRACT SCY-078 (formerly MK-3118) is a novel orally active inhibitor of fungal β-(1,3)-glucan synthase (GS). SCY-078 is a derivative of enfumafungin and is structurally distinct from the echinocandin class of antifungal agents. We evaluated the in vitro activity of this compound against wild-type (WT) and echinocandin-resistant isolates containing mutations in the FKS genes of Candida spp. Against 36 Candida spp. FKS mutants tested, 30 (83.3%) were non-WT to 1 or more echinocandins, and only 9 (25.0%) were non-WT (MIC, >WT-upper limit) to SCY-078. Among C. glabrata isolates carrying FKS alterations, 84.0% were non-WT to the echinocandins versus only 24.0% for SCY-078. In contrast to the echinocandin comparators, the activity of SCY-078 was minimally affected by the presence of FKS mutations, suggesting that this agent is useful in the treatment of Candida infections due to echinocandin-resistant strains.

scholarly journals In Vitro Activity of Ibrexafungerp, a Novel Glucan Synthase Inhibitor against Candida glabrata Isolates with FKS Mutations

2019 ◽  
Vol 63 (11) ◽  
Author(s):  
Natalie S. Nunnally ◽  
Kizee A. Etienne ◽  
David Angulo ◽  
Shawn R. Lockhart ◽  
Elizabeth L. Berkow
Keyword(s):  
Candida Glabrata ◽  
Vitro Activity ◽  
Good Activity ◽  
In Vitro Activity ◽  
Broth Microdilution ◽  
Glucan Synthase ◽  
Content Type ◽  
Synthase Inhibitor

ABSTRACT Ibrexafungerp is a first-in-class glucan synthase inhibitor. In vitro activity was determined for 89 Candida glabrata isolates with molecularly identified FKS1 or FKS2 mutations conferring resistance to the echinocandins. All isolates were resistant to at least one echinocandin (i.e., anidulafungin, caspofungin, or micafungin) by broth microdilution. Results for ibrexafungerp were compared with those for each echinocandin. Ibrexafungerp had good activity against all echinocandin-resistant C. glabrata isolates.

scholarly journals Comparison ofIn VitroAntifungal Activities of Efinaconazole and Currently Available Antifungal Agents against a Variety of Pathogenic Fungi Associated with Onychomycosis

2013 ◽  
Vol 57 (4) ◽  
pp. 1610-1616 ◽  
Author(s):  
William J. Jo Siu ◽  
Yoshiyuki Tatsumi ◽  
Hisato Senda ◽  
Radhakrishnan Pillai ◽  
Takashi Nakamura ◽  
...  
Keyword(s):  
Antifungal Agents ◽  
Trichophyton Rubrum ◽  
Yeast Species ◽  
Pathogenic Fungi ◽  
Trichophyton Mentagrophytes ◽  
Antifungal Drugs ◽  
Content Type ◽  
Comprehensive Survey ◽  
Nail Infection

ABSTRACTOnychomycosis is a common fungal nail infection in adults that is difficult to treat. Thein vitroantifungal activity of efinaconazole, a novel triazole antifungal, was evaluated in recent clinical isolates ofTrichophyton rubrum,Trichophyton mentagrophytes, andCandida albicans, common causative onychomycosis pathogens. In a comprehensive survey of 1,493 isolates, efinaconazole MICs againstT. rubrumandT. mentagrophytesranged from ≤0.002 to 0.06 μg/ml, with 90% of isolates inhibited (MIC90) at 0.008 and 0.015 μg/ml, respectively. Efinaconazole MICs against 105C. albicansisolates ranged from ≤0.0005 to >0.25 μg/ml, with 50% of isolates inhibited (MIC50) by 0.001 and 0.004 μg/ml at 24 and 48 h, respectively. Efinaconazole potency against these organisms was similar to or greater than those of antifungal drugs currently used in onychomycosis, including amorolfine, ciclopirox, itraconazole, and terbinafine. In 13T. rubrumtoenail isolates from onychomycosis patients who were treated daily with topical efinaconazole for 48 weeks, there were no apparent increases in susceptibility, suggesting low potential for dermatophytes to develop resistance to efinaconazole. The activity of efinaconazole was further evaluated in another 8 dermatophyte, 15 nondermatophyte, and 10 yeast species (a total of 109 isolates from research repositories). Efinaconazole was active againstTrichophyton,Microsporum,Epidermophyton,Acremonium,Fusarium,Paecilomyces,Pseudallescheria,Scopulariopsis,Aspergillus,Cryptococcus,Trichosporon, andCandidaand compared favorably to other antifungal drugs. In conclusion, efinaconazole is a potent antifungal with a broad spectrum of activity that may have clinical applications in onychomycosis and other mycoses.

In vitro antifungal and fungicidal activities and erythrocyte toxicities of cyclic lipodepsinonapeptides produced by Pseudomonas syringae pv. syringae.

1996 ◽  
Vol 40 (12) ◽  
pp. 2710-2713 ◽  
Author(s):  
K N Sorensen ◽  
K H Kim ◽  
J Y Takemoto
Keyword(s):  
Pseudomonas Syringae ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Antifungal Drugs ◽  
Fungal Resistance ◽  
Broth Microdilution ◽  
Antifungal Activities ◽  
Syringomycin E ◽  
Lead Compounds

Recent increases in fungal infections, the few available antifungal drugs, and increasing fungal resistance to the available antifungal drugs have resulted in a broadening of the search for new antifungal agents. Strains of Pseudomonas syringae pv. syringae produce cyclic lipodepsinonapeptides with antifungal activity. The in vitro antifungal and fungicidal activities of three cyclic lipodepsinonapeptides (syringomycin E, syringotoxin B, and syringostatin A) against medically important isolates were evaluated by a standard broth microdilution susceptibility method. Erythrocyte toxicities were also evaluated. All three compounds showed broad antifungal activities and fungicidal actions against most of the fungi tested. Overall, the cyclic lipodepsinonapeptides were more effective against yeasts than against the filamentous fungi. Syringomycin E and syringostatin A had very similar antifungal activities (2.5 to > 40 micrograms/ml) and erythrocyte toxicities. Syringotoxin B was generally less active (0.8 to 200 micrograms/ml) than syringomycin E and syringostatin A against most fungi and was less toxic to erythrocytes. With opportunities for modification, these compounds are potential lead compounds for improved antifungal agents.

scholarly journals In Vitro Antifungal Susceptibility Profiles of 12 Antifungal Drugs against 55 Trichophyton schoenleinii Isolates from Tinea Capitis Favosa Patients in Iran, Turkey, and China

2016 ◽  
Vol 61 (2) ◽  
Author(s):  
Shuwen Deng ◽  
Saham Ansari ◽  
Macit Ilkit ◽  
Haleh Rafati ◽  
Mohammad T. Hedayati ◽  
...  
Keyword(s):  
Antifungal Agents ◽  
Antifungal Susceptibility ◽  
Antifungal Drugs ◽  
Content Type ◽  
Microdilution Method ◽  
Broth Microdilution Method ◽  
In Vitro Antifungal Susceptibility ◽  
Trichophyton Schoenleinii ◽  
Susceptibility Profiles

ABSTRACT Trichophyton schoenleinii is an anthropophilic dermatophyte mainly causing tinea favosa of the scalp in certain regions of the world, especially Africa and Asia. We investigated the in vitro susceptibilities of 55 T. schoenleinii isolates collected over the last 30 years from Iran, Turkey, and China to 12 antifungals using the CLSI broth microdilution method. Our results revealed that terbinafine and ketoconazole were the most potent antifungal agents among those tested, independently of the geographic regions where strains were isolated.

scholarly journals Evaluation of the Antifungal Activity of the Novel Oral Glucan Synthase Inhibitor SCY-078, Singly and in Combination, for the Treatment of Invasive Aspergillosis

2018 ◽  
Vol 62 (6) ◽  
Author(s):  
M. Ghannoum ◽  
L. Long ◽  
E. L. Larkin ◽  
N. Isham ◽  
R. Sherif ◽  
...  
Keyword(s):  
Invasive Aspergillosis ◽  
Amphotericin B ◽  
Synergistic Activity ◽  
Minimum Effective Concentration ◽  
Glucan Synthase ◽  
Content Type ◽  
Fungistatic Activity ◽  
Synthase Inhibitor

ABSTRACT Invasive aspergillosis remains a major cause of death among the immunocompromised population and those receiving long-term immunosuppressive therapy. In light of increased azole resistance, variable outcomes with existing echinocandin monotherapy and combination therapy, and persistent high mortality rates, new antifungal agents for the treatment of invasive aspergillosis are clearly needed. SCY-078 is the first-in-class triterpenoid antifungal, a novel class of glucan synthase inhibitors with broad in vitro and in vivo activity against a broad spectrum of Candida and Aspergillus species. In vitro testing of clinical strains of Aspergillus fumigatus and non- fumigatus Aspergillus strains showed that SCY-078 had potent fungistatic activity (minimum effective concentration for 90% of strains tested = 0.125 μg/ml) compared with the activities of amphotericin B (MIC 90 = 8 μg/ml) and voriconazole (MIC 90 = 2 μg/ml). Testing of SCY-078 in combination with isavuconazole or voriconazole demonstrated synergistic activity against the majority of the azole-susceptible strains tested, and SCY-078 in combination with amphotericin B was synergistic against the azole-susceptible strains, as well as one known resistant cyp51A mutant. SCY-078 may be an important additional antifungal for first-line or salvage monotherapy or combination treatment of invasive aspergillosis.

scholarly journals In VitroActivity of Isavuconazole against Rasamsonia Species

2016 ◽  
Vol 60 (11) ◽  
pp. 6890-6891 ◽  
Author(s):  
J. Steinmann ◽  
S. Dittmer ◽  
J. Houbraken ◽  
J. Buer ◽  
P.-M. Rath
Keyword(s):  
Species Complex ◽  
Antifungal Agents ◽  
Effective Concentration ◽  
Antifungal Drugs ◽  
The Novel ◽  
Large Collection ◽  
Minimum Effective Concentration ◽  
Content Type

ABSTRACTThein vitrosusceptibilities to the novel triazole isavuconazole and six other antifungal agents of a large collection ofRasamsoniaisolates (n= 47) belonging to seven species were determined. Isavuconazole and voriconazole had noin vitroactivity (MIC, >32 mg/liter) against isolates of theRasamsoniaargillaceaspecies complex. The echinocandins were the most potent antifungal drugs against all of the isolates tested (minimum effective concentration, ≤0.19 mg/liter).

scholarly journals In vitro Efficacy of Novel Glucan Synthase Inhibitor, Ibrexafungerp (SCY-078), Against Multidrug- and Pan-resistant Candida auris Isolates from the Outbreak in New York

2019 ◽  
Author(s):  
Yan Chun Zhu ◽  
Stephen A. Barat ◽  
Katyna Borroto-Esoda ◽  
David Angulo ◽  
Sudha Chaturvedi ◽  
...  
Keyword(s):  
New York ◽  
Antifungal Drugs ◽  
Candida Auris ◽  
Glucan Synthase ◽  
Variable Resistance ◽  
Synthase Inhibitor

AbstractWe report low MIC50 of Ibrexafungerp (SCY-078) for 102 Candida auris clinical and surveillance isolates from outbreak in New York. The group included C. auris with a variable resistance to antifungal drugs. Five pan-resistant C. auris isolates were susceptible to Ibrexafungerp with low MIC50 range of 0.12-1 µg/ml.

scholarly journals Potency of Olorofim (F901318) Compared to Contemporary Antifungal Agents against Clinical Aspergillus fumigatus Isolates and Review of Azole Resistance Phenotype and Genotype Epidemiology in China

2021 ◽  
Vol 65 (5) ◽  
Author(s):  
Huilin Su ◽  
Min Zhu ◽  
Clement Kin-Ming Tsui ◽  
Henrich van der Lee ◽  
Marlou Tehupeiory-Kooreman ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Drug Targets ◽  
Antifungal Agents ◽  
Single Point ◽  
Resistance Mechanism ◽  
Antifungal Drugs ◽  
Single Point Mutation ◽  
Content Type ◽  
Novel Drug

ABSTRACT Triazole resistance in Aspergillus fumigatus is an increasing worldwide problem that causes major challenges in the management of aspergillosis. New antifungal drugs are needed, with novel targets, that are effective in triazole-resistant infection. In this study, we retrospectively evaluated the potency of the novel drug olorofim compared to contemporary antifungal agents against 111 clinical A. fumigatus isolates collected from Huashan Hospital, Shanghai, China, using EUCAST methodology, and we reviewed the literature on triazole-resistant A. fumigatus (TRAF) published between 1966 and 2020 in China. Olorofim was active in vitro against all tested A. fumigatus isolates, with a MIC90 of 0.031 mg/liter (range, 0.008 to 0.062 mg/liter). For 4 triazole-resistant A. fumigatus isolates, the olorofim MIC ranged between 0.016 and 0.062 mg/liter. The reported rates of TRAF in China are 2.5 to 5.56% for clinical isolates and 0 to 1.4% for environmental isolates. TR34/L98H/S297T/F495I is the predominant resistance mechanism, followed by TR34/L98H. Non-TR-mediated TRAF isolates, mostly harboring a cyp51A single point mutation, showed greater genetic diversity than TR-mediated resistant isolates. Resistance due to TR34/L98H and TR34/L98H/S297T/F495I mutations among TRAF isolates might have evolved from separate local isolates in China. Continuous isolation of TRAF in China underscores the need for systematic resistance surveillance as well as the need for novel drug targets, such as olorofim.

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