scholarly journals Novel Antifungal Compounds Discovered in Medicines for Malaria Venture’s Malaria Box

mSphere ◽  
2018 ◽  
Vol 3 (2) ◽  
Author(s):  
Eric H. Jung ◽  
David J. Meyers ◽  
Jürgen Bosch ◽  
Arturo Casadevall
Keyword(s):  
Candida Albicans ◽  
Antifungal Activity ◽  
Cryptococcus Neoformans ◽  
Fungal Pathogens ◽  
Pathogenic Fungi ◽  
Cryptococcus Gattii ◽  
Antifungal Drugs ◽  
Resistant Bacteria ◽  
Animal Cells ◽  
Malaria Box

ABSTRACTSimilarities in fungal and animal cells make antifungal discovery efforts more difficult than those for other classes of antimicrobial drugs. Currently, there are only three major classes of antifungal drugs used for the treatment of systemic fungal diseases: polyenes, azoles, and echinocandins. Even in situations where the offending fungal organism is susceptible to the available drugs, treatment courses can be lengthy and unsatisfactory, since eradication of infection is often very difficult, especially in individuals with impaired immunity. Consequently, there is a need for new and more effective antifungal drugs. We have identified compounds with significant antifungal activity in the Malaria Box (Medicines for Malaria Ventures, Geneva, Switzerland) that have higher efficacy than some of the currently used antifungal drugs. Our best candidate, MMV665943 (IUPAC name 4-[6-[[2-(4-aminophenyl)-3H-benzimidazol-5-yl]methyl]-1H-benzimidazol-2-yl]aniline), here referred to as DM262, showed 16- to 32-fold-higher activity than fluconazole againstCryptococcus neoformans. There was also significant antifungal activity in other fungal species with known antifungal resistance, such asLomentospora prolificansandCryptococcus gattii. Antifungal activity was also observed against a common fungus,Candida albicans. These results are important because they offer a potentially new class of antifungal drugs and the repurposing of currently available therapeutics.IMPORTANCEMuch like the recent increase in drug-resistant bacteria, there is a rise in antifungal-resistant strains of pathogenic fungi. There is a need for novel and more potent antifungal therapeutics. Consequently, we investigated a mixed library of drug-like and probe-like compounds with activity inPlasmodiumspp. for activity against two common fungal pathogens,Cryptococcus neoformansandCandida albicans, along with two less common pathogenic species,Lomentospora prolificansandCryptococcus gattii. We uncover a previously uncharacterized drug with higher broad-spectrum antifungal activity than some current treatments. Our findings may eventually lead to a compound added to the arsenal of antifungal therapeutics.

scholarly journals Antifungal Activity of the Essential Oil of Echinops kebericho Mesfin: An In Vitro Study

2020 ◽  
Vol 2020 ◽  
pp. 1-7
Author(s):  
Tamirat Bekele Beressa ◽  
Serawit Deyno ◽  
Paul E. Alele
Keyword(s):  
Candida Albicans ◽  
Antifungal Activity ◽  
Essential Oil ◽  
Cryptococcus Neoformans ◽  
Antioxidant Properties ◽  
Pathogenic Fungi ◽  
Diffusion Method ◽  
Potential Candidate ◽  
Standard Drug

Background. Echinops kebericho is an endemic medicinal plant in Ethiopia widely used in the treatment of infectious and noninfectious diseases. Essential oils are known for their antibacterial, antifungal, antiviral, insecticidal, and antioxidant properties. This study evaluated the antifungal activity of essential oil from E. kebericho against four common pathogenic fungi and two standard strains. Methods. The essential oil was obtained by hydrodistillation. The antifungal screening was done by agar well diffusion method. Minimal inhibitory concentrations (MICs) were determined by broth microdilution. Minimal fungicidal concentrations (MFCs) were determined by subculturing fungal strains with no visible growth onto a Sabouraud dextrose agar (SDA) plate. Results. Candida albicans and Cryptococcus neoformans were highly sensitive while Aspergillus flavus did not show sensitivity up to 1 mg/ml of essential oil; MICs ranged from 0.083 mg/ml to 0.208 mg/ml. Concentration and fungal species showed significant dose-dependent associations ( p < 0.0001 ) with antifungal activity. The MICs of essential oil were comparable to those of the standard drug (fluconazole) against C. glabrata and C. krusei. The lowest MFC of the essential oil was observed against Candida parapsilosis (0.145 mg/ml) while the highest MFC was against Candida krusei (0.667 mg/ml). Conclusion. Echinops kebericho essential oil showed noteworthy antifungal activity against Cryptococcus neoformans, Candida albicans, and Candida glabrata and could be a potential candidate for further antifungal drug development.

Antifungal activity of promethazine and chlorpromazine against planktonic cells and biofilms of Cryptococcus neoformans/Cryptococcus gattii complex species

2020 ◽  
Vol 58 (7) ◽  
pp. 906-912
Author(s):  
Raimunda Sâmia Nogueira Brilhante ◽  
Wilker Jose Perez Gotay ◽  
Vandbergue Santos Pereira ◽  
Jonathas Sales de Oliveira ◽  
Waldemiro Aquino Pereira-Neto ◽  
...  
Keyword(s):  
Antifungal Activity ◽  
Cryptococcus Neoformans ◽  
Metabolic Activity ◽  
Biofilm Formation ◽  
Fungal Pathogens ◽  
Cryptococcus Gattii ◽  
Planktonic Cells ◽  
Complex Species ◽  
Cryptococcus Spp

Abstract Cryptococcus neoformans/Cryptococcus gattii are fungal pathogens that affect the central nervous system, mainly in immunocompromised individuals. Due to the limited pharmacological arsenal available for the treatment of cryptococcosis associated with cases of antifungal resistance of Cryptococcus spp. reported in some studies, the search for new compounds with antifungal potential becomes relevant. Thus, the objective of this study was to evaluate the inhibitory effect of phenothiazines (promethazine and chlorpromazine) on C. neoformans/C. gattii planktonic cells and biofilms. In vitro planktonic susceptibility testing was performed using the broth microdilution assay. The effect of phenothiazines was evaluated against biofilm formation and mature Cryptococcus biofilms. Biofilm morphology and ultrastructure were also evaluated by scanning electron microscopy. Promethazine and chlorpromazine showed antifungal activity against planktonic cells, with minimum inhibitory concentrations of 8–32 μg/ml and 4–16 μg/ml, respectively. As for biofilm formation, phenothiazines reduced biomass by 60% and metabolic activity by 90% at 64 μg/ml; while in mature biofilms, reductions of 85% and 90% in biomass and metabolic activity, respectively, were observed at 1024 μg/ml. Promethazine and chlorpromazine were also able to disrupt and fragment biofilms. In conclusion, promethazine and chlorpromazine have antifungal activity against planktonic cells and biofilms of Cryptococcus spp. These data show the potential of promethazine and chlorpromazine as antibiofilm drugs.

scholarly journals Antifungal activity of 2,3-diphenyl-2,3-dihydro-1,3-thiaza-4-ones against two human pathogenic fungi

2020 ◽  
Author(s):  
Livia Liporagi-Lopes ◽  
Hany F. Sobhi ◽  
Lee J. Silverberg ◽  
Radames J.B. Cordero ◽  
Arturo Casadevall
Keyword(s):  
Antifungal Activity ◽  
Cell Surface ◽  
Cryptococcus Neoformans ◽  
Pathogenic Fungi ◽  
Fungal Species ◽  
Antifungal Drugs ◽  
Fungal Diseases ◽  
Invasive Fungal Diseases ◽  
Current Therapies ◽  
New Compounds

ABSTRACTInvasive fungal diseases are prevalent in immunocompromised individuals in whom current therapies often provide suboptimal results. Additionally, the increased resistance to the available antifungal drugs necessitates a search for new compounds. This study reports the antifungal activity of six 5-, 6-, and 7-membered 2,3-diphenyl-2,3-dihydro-1,3-thiaza-4-ones against Lomentospora prolificans and Cryptococcus neoformans. Our data showed that some of the compounds tested had a low MIC and damage on the cell surface of the tested fungal species.

scholarly journals Aktivitas Antijamur Ekstrak Biji Pepaya (Carica Papaya L.) Varietas Bangkok

2021 ◽  
Vol 36 (1) ◽  
pp. 14-18
Author(s):  
Forman Erwin Siagian ◽  
Dena Carolina Sabono ◽  
Muhammad Alfarabi
Keyword(s):  
Candida Albicans ◽  
Antifungal Activity ◽  
Cryptococcus Neoformans ◽  
Organic Waste ◽  
Carica Papaya ◽  
Inhibition Zone ◽  
Seed Extract ◽  
Antifungal Drugs ◽  
Opportunistic Fungi ◽  
Candida Sp

Abstrak Candida sp. dan Cryptococcus sp. merupakan jamur oportunistik yang dapat menyebabkan penyakit pada manusia dan dapat berakibat fatal jika tidak ditangani dengan cepat dan tepat. Saat ini terdapat permasalahan yaitu resistensi antijamur dan jenis terapi terhadap jamur yang terbatas. Terdapatnya bahan alam yang melimpah di Indonesia menjadi suatu potensi untuk mengembangkan obat anti jamur baru yang memiliki efektivitas tinggi, efek samping yang minimal, dan murah. Salah satu bahan alam yang belum tereksplorasi untuk antijamur adalah biji pepaya varietas bangkok. Biji pepaya selama ini lebih banyak menjadi limbah organik. Oleh karena hal tersebut, tujuan dari penelitian ini adalah untuk menguji aktivitas antijamur dari ekstrak biji pepaya bangkok (Carica papaya L.). Jamur yang digunakan pada penelitian ini adalah Candida albicans dan Cryptococcus neoformans. Metode yang digunakan adalah perhitungan zona hambat pada sumur di cawan petri. Hasil penelitian menunjukkan bahwa tidak terdapat zona hambat pada media yang terdapat C. albicans dan C. neoformans.  Dapat disimpulkan, ekstrak biji papaya tidak memiliki aktivitas antijamur terhadap kedua jamur tersebut. Kata kunci: Pepaya bangkok, Antijamur, Bahan alam Abstract Candida sp. and Cryptococcus sp. are opportunistic fungi that can be fatal disease in humans if not treated properly. However, resistance of antifungal drugs have been emerged, therefore limit their benefit for therapy. Many natural products in Indonesia have potential to be established for new antifungal drugs that have high effectiveness, minimal side effects, and inexpensive. Papaya bangkok seed has not been explored for its antifungal activity. This seed become more organic waste. The aim of this study was to test antifungal activity of various papaya bangkok seed extract concentrations. We measured the inhibiton zone of papaya extract to Candida albicans and Cryptococcus neoformans. Result showed no inhibition zone for each seed extract concentrations. Papaya bangkok seed extract has not antifungal activity. Keywords: Papaya bangkok, antifungal, natural product

scholarly journals Revisiting the Vital Drivers and Mechanisms of β-Glucan Masking in Human Fungal Pathogen, Candida albicans

Pathogens ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 942
Author(s):  
Saif Hameed ◽  
Sandeep Hans ◽  
Shweta Singh ◽  
Ruby Dhiman ◽  
Ross Monasky ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Fungal Pathogens ◽  
Pathogenic Fungi ◽  
Antifungal Drugs ◽  
Immune Recognition ◽  
Fungal Cell ◽  
Distinctive Features ◽  
Host Immune Responses ◽  
Human Fungal Pathogen ◽  
Buried Layers

Among the several human fungal pathogens, Candida genus represents one of the most implicated in the clinical scenario. There exist several distinctive features that govern the establishment of Candida infections in addition to their capacity to adapt to multiple stress conditions inside humans which also include evasion of host immune responses. The complex fungal cell wall of the prevalent pathogen, Candida albicans, is one of the main targets of antifungal drugs and recognized by host immune cells. The wall consists of tiered arrangement of an outer thin but dense covering of mannan and inner buried layers of β-glucan and chitin. However, the pathogenic fungi adopt strategies to evade immune recognition by masking these molecules. This capacity to camouflage the immunogenic polysaccharide β-glucan from the host is a key virulence factor of C. albicans. The present review is an attempt to collate various underlying factors and mechanisms involved in Candida β-glucan masking from the available pool of knowledge and provide a comprehensive understanding. This will further improve therapeutic approaches to candidiasis by identifying new antifungal targets that blocks fungal immune evasion.

Efficacy of Novel Schiff base Derivatives as Antifungal Compounds in Combination with Approved Drugs Against Candida Albicans

2019 ◽  
Vol 15 (6) ◽  
pp. 648-658 ◽  
Author(s):  
Manzoor Ahmad Malik ◽  
Shabir Ahmad Lone ◽  
Parveez Gull ◽  
Ovas Ahmad Dar ◽  
Mohmmad Younus Wani ◽  
...  
Keyword(s):  
Schiff Base ◽  
Candida Albicans ◽  
Antifungal Activity ◽  
Fungal Infections ◽  
Total Sterol ◽  
Antifungal Drugs ◽  
New Drugs ◽  
Ergosterol Biosynthesis ◽  
Dependent Manner ◽  
Schiff Base Derivatives

Background: The increasing incidence of fungal infections, especially caused by Candida albicans, and their increasing drug resistance has drastically increased in recent years. Therefore, not only new drugs but also alternative treatment strategies are promptly required. Methods: We previously reported on the synergistic interaction of some azole and non-azole compounds with fluconazole for combination antifungal therapy. In this study, we synthesized some non-azole Schiff-base derivatives and evaluated their antifungal activity profile alone and in combination with the most commonly used antifungal drugs- fluconazole (FLC) and amphotericin B (AmB) against four drug susceptible, three FLC resistant and three AmB resistant clinically isolated Candida albicans strains. To further analyze the mechanism of antifungal action of these compounds, we quantified total sterol contents in FLC-susceptible and resistant C. albicans isolates. Results: A pyrimidine ring-containing derivative SB5 showed the most potent antifungal activity against all the tested strains. After combining these compounds with FLC and AmB, 76% combinations were either synergistic or additive while as the rest of the combinations were indifferent. Interestingly, none of the combinations was antagonistic, either with FLC or AmB. Results interpreted from fractional inhibitory concentration index (FICI) and isobolograms revealed 4-10-fold reduction in MIC values for synergistic combinations. These compounds also inhibit ergosterol biosynthesis in a concentration-dependent manner, supported by the results from docking studies. Conclusion: The results of the studies conducted advocate the potential of these compounds as new antifungal drugs. However, further studies are required to understand the other mechanisms and in vivo efficacy and toxicity of these compounds.

Phytochemical Constituents of Tulbaghia violacea Harv Extract and its Antifungal Potential Against Cryptococcus neoformans and Cryptococcus gattii

2019 ◽  
Vol 9 (4) ◽  
pp. 330-340
Author(s):  
Mitradev Pattoo ◽  
Vuyokazi Belewa ◽  
Benesh Munilal Somai
Keyword(s):  
Antifungal Activity ◽  
Cryptococcus Neoformans ◽  
Antifungal Therapy ◽  
Developing World ◽  
Chemical Constituents ◽  
Cryptococcus Gattii ◽  
Plant Part ◽  
Aqueous Extracts ◽  
Antifungal Activities ◽  
Antifungal Potential

Background:In both the developed and developing world, the mortality rates of people afflicted with cryptococcosis are unacceptably high despite the availability of antifungal therapy. The disease is caused by Cryptococcus neoformans (predominantly in immunocompromised individuals) and by Cryptococcus gattii. Globally the disease is estimated to cause around 600,000 deaths annually. Antifungal therapy is available, but in the developing world, may be unaffordable to many people, there is an increasing threat of resistance to the available drugs and our repertoire of antifungal drugs is very limited. Consequently, more research has been focusing on the use of medicinal plants as therapeutic agents. The originality of the current study is that although Tulbaghia violacea is a well-documented medicinal plant, the chemical composition of aqueous extracts and their antifungal potential against pathogenic yeasts are unknown. This is the first study that evaluates the chemical constituents of aqueous T. violacea root, leaf, rhizome and tuber extracts and their corresponding antifungal activities against C. neoformans and C. gattii.Objectives:The study aimed to investigate the phytochemical composition and antifungal potential of Tulbaghia violacea root, leaf, rhizome and tuber extracts against Cryptococcus neoformans and Cryptococcus gattii.Methods:Roots, leaves, rhizomes and tubers were extracted with water only for 48 h at room temperature with continuous shaking. Extracts were filter sterilized, freeze-dried and, chemically analyzed for saponin, flavonol, phenolic and tannin content. Chemical constituents of each extract were also identified by GC-MS analysis. The Minimum Inhibitory Concentration (MIC) of suitably diluted extracts of each plant part were also performed against C. neoformans and C. gattii, yeast pathogens commonly associated with HIV/AIDS sufferers.Results:Phytochemical analysis showed different concentrations of saponins (between 1023 and 2896.73 µg/ml), phenolics (between 16.48 and 51.58 µg/ml) and tannins (between 122.30 and 543.07 µg/ml) present in the different extracts. No flavonols were detected. GC-MS analysis identified a complex mixture of phytochemicals composed predominantly of sulphide, pyran, furan and ketone containing compounds to be present in the different plant parts. All extracts were dominated by the presence of 4 H-pyran-4-one, 2,3-dihydro-3,5-dihydroxy-6-methyl, a pyran known to have antifungal properties. Although the root, leaf, rhizome and tuber extracts exhibited antifungal activities against both fungi, the rhizome and tuber extract were found to possess the lowest MIC’s of 1.25 mg/ml and 2.5 mg/ml against Cryptococcus neoformans and Cryptococcus gattii respectively.Conclusion:T. violacea extracts have a complex constituent of phytochemicals and each plant part exhibited a strong antifungal activity against C. neoformans and C. gattii. The rhizome and tuber extracts showed the highest antifungal activity against C. neoformans and C. gattii respectively. Thus, T. violacea aqueous extracts are strong candidates for further development into an antifungal chemotherapeutic agent.

scholarly journals Dectin-2-Targeted Antifungal Liposomes Exhibit Enhanced Efficacy

mSphere ◽  
2019 ◽  
Vol 4 (5) ◽  
Author(s):  
Suresh Ambati ◽  
Emma C. Ellis ◽  
Jianfeng Lin ◽  
Xiaorong Lin ◽  
Zachary A. Lewis ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Aspergillus Fumigatus ◽  
Effective Dose ◽  
Cryptococcus Neoformans ◽  
Amphotericin B ◽  
Antifungal Drugs ◽  
Extracellular Matrices ◽  
Content Type ◽  
Order Of Magnitude ◽  
Life Threatening

ABSTRACT Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus cause life-threatening candidiasis, cryptococcosis, and aspergillosis, resulting in several hundred thousand deaths annually. The patients at the greatest risk of developing these life-threatening invasive fungal infections have weakened immune systems. The vulnerable population is increasing due to rising numbers of immunocompromised individuals as a result of HIV infection or immunosuppressed individuals receiving anticancer therapies and/or stem cell or organ transplants. While patients are treated with antifungals such as amphotericin B, all antifungals have serious limitations due to lack of sufficient fungicidal effect and/or host toxicity. Even with treatment, 1-year survival rates are low. We explored methods of increasing drug effectiveness by designing fungicide-loaded liposomes specifically targeted to fungal cells. Most pathogenic fungi are encased in cell walls and exopolysaccharide matrices rich in mannans. Dectin-2 is a mammalian innate immune membrane receptor that binds as a dimer to mannans and signals fungal infection. We coated amphotericin-loaded liposomes with monomers of Dectin-2’s mannan-binding domain, sDectin-2. sDectin monomers were free to float in the lipid membrane and form dimers that bind mannan substrates. sDectin-2-coated liposomes bound orders of magnitude more efficiently to the extracellular matrices of several developmental stages of C. albicans, C. neoformans, and A. fumigatus than untargeted control liposomes. Dectin-2-coated amphotericin B-loaded liposomes reduced the growth and viability of all three species more than an order of magnitude more efficiently than untargeted control liposomes and dramatically decreased the effective dose. Future efforts focus on examining pan-antifungal targeted liposomal drugs in animal models of fungal diseases. IMPORTANCE Invasive fungal diseases caused by Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus have mortality rates ranging from 10 to 95%. Individual patient costs may exceed $100,000 in the United States. All antifungals in current use have serious limitations due to host toxicity and/or insufficient fungal cell killing that results in recurrent infections. Few new antifungal drugs have been introduced in the last 2 decades. Hence, there is a critical need for improved antifungal therapeutics. By targeting antifungal-loaded liposomes to α-mannans in the extracellular matrices secreted by these fungi, we dramatically reduced the effective dose of drug. Dectin-2-coated liposomes loaded with amphotericin B bound 50- to 150-fold more strongly to C. albicans, C. neoformans, and A. fumigatus than untargeted liposomes and killed these fungi more than an order of magnitude more efficiently. Targeting drug-loaded liposomes specifically to fungal cells has the potential to greatly enhance the efficacy of most antifungal drugs.

Biosynthesis of selenium nanoparticles by Aspergillus flavus and Candida albicans and comparison of their effects with antifungal drugs

2021 ◽  
Author(s):  
Mahdi Hosseini Bafghi ◽  
Razieh Nazari ◽  
Majid Darroudi ◽  
Mohsen Zargar ◽  
Hossein Zarrinfar
Keyword(s):  
Candida Albicans ◽  
Aspergillus Flavus ◽  
Fungal Pathogens ◽  
Chemical Properties ◽  
Cost Effective ◽  
Antifungal Drugs ◽  
Selenium Nanoparticles ◽  
Fungal Strains ◽  
Vis Spectroscopy ◽  
Physical And Chemical

Abstract Biosynthesis of nanoparticles can stand as a replacement for the available chemical and physical methods by offering new procedures as green syntheses that have proved to be simple, biocompatible, safe, and cost-effective. Considering how nanoparticles with a size of 1 to 100 nanometers contain unique physical and chemical properties, recent reports are indicative of observing the antifungal qualities of selenium nanoparticles (Se-NPs). Recently, the observance of antifungal resistance towards different species of these fungi is often reported. Therefore, due to the antifungal effects of biological nanoparticles, this study aimed to investigate the exertion of these nanoparticles and evaluate their effects on the growth of fungal pathogens. Se-NPs were biosynthesized by the application of wet reduction method, which included specific concentrations of Aspergillus flavus and Candida albicans. The presence of nanoparticles was confirmed by methods such as UV-Vis spectroscopy, FT-IR analysis, and FESEM electron microscope that involved FESEM and EDAX diagram. The fungal strains were cultured in sabouraud dextrose agar medium to perform the sensitivity test based on the minimum inhibitory concentration (MIC) method in duplicate. The utilization of Se-NPs at concentrations of 1 µg/ ml and below resulted in zero growth of fungal agents. However, their growth was inhibited by antifungal drugs at concentrations of 2 µg/ ml and higher. Based on the obtained results, biological nanoparticles produced by fungal agents at different concentrations exhibited favorable inhibitory effects on the growth of fungal strains.

Sordarins: In Vitro Activities of New Antifungal Derivatives against Pathogenic Yeasts, Pneumocystis carinii, and Filamentous Fungi

1998 ◽  
Vol 42 (11) ◽  
pp. 2863-2869 ◽  
Author(s):  
E. Herreros ◽  
C. M. Martinez ◽  
M. J. Almela ◽  
M. S. Marriott ◽  
F. Gomez De Las Heras ◽  
...  
Keyword(s):  
Cryptococcus Neoformans ◽  
Filamentous Fungi ◽  
Fungal Pathogens ◽  
Pneumocystis Carinii ◽  
Pathogenic Fungi ◽  
Pseudallescheria Boydii ◽  
Absidia Corymbifera ◽  
Wide Range ◽  
Blastoschizomyces Capitatus

ABSTRACT GM 193663, GM 211676, GM 222712, and GM 237354 are new semisynthetic derivatives of the sordarin class. The in vitro antifungal activities of GM 193663, GM 211676, GM 222712, and GM 237354 against 111 clinical yeast isolates of Candida albicans,Candida kefyr, Candida glabrata, Candida parapsilosis, Candida krusei, and Cryptococcus neoformans were compared. The in vitro activities of some of these compounds against Pneumocystis carinii, 20 isolates each of Aspergillus fumigatus and Aspergillus flavus, and 30 isolates of emerging less-common mold pathogens and dermatophytes were also compared. The MICs of GM 193663, GM 211676, GM 222712, and GM 237354 at which 90% of the isolates were inhibited (MIC90s) were 0.03, 0.03, 0.004, and 0.015 μg/ml, respectively, for C. albicans, including strains with decreased susceptibility to fluconazole; 0.5, 0.5, 0.06, and 0.12 μg/ml, respectively, for C. tropicalis; and 0.004, 0.015, 0.008, and 0.03 μg/ml, respectively, forC. kefyr. GM 222712 and GM 237354 were the most active compounds against C. glabrata, C. parapsilosis, and Cryptococcus neoformans. AgainstC. glabrata and C. parapsilosis, the MIC90s of GM 222712 and GM 237354 were 0.5 and 4 μg/ml and 1 and 16 μg/ml, respectively. The MIC90s of GM 222712 and GM 237354 againstCryptococcus neoformans were 0.5 and 0.25 μg/ml, respectively. GM 193663, GM 211676, GM 222712, and GM 237354 were extremely active against P. carinii. The efficacies of sordarin derivatives against this organism were determined by measuring the inhibition of the uptake and incorporation of radiolabelled methionine into newly synthesized proteins. All compounds tested showed 50% inhibitory concentrations of <0.008 μg/ml. Against A. flavus and A. fumigatus, the MIC90s of GM 222712 and GM 237354 were 1 and 32 μg/ml and 32 and >64 μg/ml, respectively. In addition, GM 237354 was tested against the most important emerging fungal pathogens which affect immunocompromised patients. Cladosporium carrioni, Pseudallescheria boydii, and the yeast-like fungi Blastoschizomyces capitatus and Geotrichum clavatum were the most susceptible of the fungi to GM 237354, with MICs ranging from ≤0.25 to 2 μg/ml. The MICs of GM 237354 against Trichosporon beigelii and the zygomycetesAbsidia corymbifera, Cunninghamella bertholletiae, and Rhizopus arrhizus ranged from ≤0.25 to 8 μg/ml. Against dermatophytes, GM 237354 MICs were ≥2 μg/ml. In summary, we concluded that some sordarin derivatives, such as GM 222712 and GM 237354, showed excellent in vitro activities against a wide range of pathogenic fungi, includingCandida spp., Cryptococcus neoformans, P. carinii, and some filamentous fungi and emerging invasive fungal pathogens.

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