Open, single-arm phase-III study to investigate the percutaneous absorption of abafungin after topical dermal application of Abafungin cream 1.0 % (YORK Pharma GmbH) in 20 patients with tinea pedis interdigitalis

开始日期2007-05-21

申办/合作机构

York Pharma Gmbh

EUCTR2006-001263-32-DE / Not yet recruitingN/A

Phase III study to evaluate the anti-mycotic efficacy of a topical Abafungin formulation in patients with tinea pedis - N.A.

开始日期2006-06-29

申办/合作机构

York Pharma Gmbh

EUCTR2005-002842-20-DE / Not yet recruitingN/A

Phase II dose ranging study to evaluate the anti-mycotic efficacy of topical Abafungin formulations in patients with tinea pedis. - N.A.

开始日期2005-09-29

申办/合作机构

York Pharma Gmbh

100 项与 SMT1 相关的临床结果

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100 项与 SMT1 相关的转化医学

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0 项与 SMT1 相关的专利（医药）

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143

项与 SMT1 相关的文献（医药）

2024-10-01·Acta Tropica

Repurposing FDA approved drugs against Sterol C-24 methyltransferase of Leishmania donovani: A dual in silico and in vitro approach

Article

作者: Kumari, Diksha ; Jamwal, Vishwani ; Singh, Kuljit ; Ansari, Md Yousuf ; Singh, Shashank K ; Singh, Ajeet ; Mujwar, Somdutt

Leishmaniasis is a disease caused by the parasite Leishmania donovani affecting populations belonging to developing countries. The present study explores drug repurposing as an innovative strategy to identify new uses for approved clinical drugs, reducing the time and cost required for drug discovery. The three-dimensional structure of Leishmania donovani Sterol C-24 methyltransferase (LdSMT) was modeled and 1615 FDA-approved drugs from the ZINC database were computationally screened to identify the potent leads. Fulvestrant, docetaxel, indocyanine green, and iohexol were shortlisted as potential leads with the highest binding affinity and fitness scores for the concerned pathogenic receptor. Molecular dynamic simulation studies showed that the macromolecular complexes of indocyanine green and iohexol with LdSMT remained stable throughout the simulation and can be further evaluated experimentally for developing an effective drug. The proposed leads have further demonstrated promising safety profiles during cytotoxicity analysis on the J774.A1 macrophage cell line. Mechanistic analysis with these two drugs also revealed significant morphological alterations in the parasite, along with reduced intracellular parasitic load. Overall, this study demonstrates the potential of drug repurposing in identifying new treatments for leishmaniasis and other diseases affecting developing countries, highlighting the importance of considering approved clinical drugs for new applications.

2024-08-14·mBio

Alternative ergosterol biosynthetic pathways confer antifungal drug resistance in the human pathogens within the Mucor species complex

Article

作者: Pérez-Arques, Carlos ; Navarro-Mendoza, María Isabel ; Heitman, Joseph ; Parker, Josie ; Xu, Ziyan ; Kelly, Steven

ABSTRACT Mucormycoses are emerging fungal infections caused by a variety of heterogeneous species within the Mucorales order. Among the Mucor species complex, Mucor circinelloides is the most frequently isolated pathogen in mucormycosis patients and despite its clinical significance, there is an absence of established genome manipulation techniques to conduct molecular pathogenesis studies. In this study, we generated a spontaneous uracil auxotrophic strain and developed a genetic transformation procedure to analyze molecular mechanisms conferring antifungal drug resistance. With this new model, phenotypic analyses of gene deletion mutants were conducted to define Erg3 and Erg6a as key biosynthetic enzymes in the M. circinelloides ergosterol pathway. Erg3 is a C-5 sterol desaturase involved in growth, sporulation, virulence, and azole susceptibility. In other fungal pathogens, erg3 mutations confer azole resistance because Erg3 catalyzes the production of a toxic diol upon azole exposure. Surprisingly, M. circinelloides produces only trace amounts of this toxic diol and yet, it is still susceptible to posaconazole and isavuconazole due to alterations in membrane sterol composition. These alterations are severely aggravated by erg3 Δ mutations, resulting in ergosterol depletion and, consequently, hypersusceptibility to azoles. We also identified Erg6a as the main C-24 sterol methyltransferase, whose activity may be partially rescued by the paralogs Erg6b and Erg6c. Loss of Erg6a function diverts ergosterol synthesis to the production of cholesta-type sterols, resulting in resistance to amphotericin B. Our findings suggest that mutations or epimutations causing loss of Erg6 function may arise during human infections, resulting in antifungal drug resistance to first-line treatments against mucormycosis. IMPORTANCE The Mucor species complex comprises a variety of opportunistic pathogens known to cause mucormycosis, a potentially lethal fungal infection with limited therapeutic options. The only effective first-line treatments against mucormycosis consist of liposomal formulations of amphotericin B and the triazoles posaconazole and isavuconazole, all of which target components within the ergosterol biosynthetic pathway. This study uncovered M. circinelloides Erg3 and Erg6a as key enzymes to produce ergosterol, a vital constituent of fungal membranes. Absence of any of those enzymes leads to decreased ergosterol and consequently, resistance to ergosterol-binding polyenes such as amphotericin B. Particularly, losing Erg6a function poses a higher threat as the ergosterol pathway is channeled into alternative sterols similar to cholesterol, which maintain membrane permeability. As a result, erg6a mutants survive within the host and disseminate the infection, indicating that Erg6a deficiency may arise during human infections and confer resistance to the most effective treatment against mucormycoses.

2024-08-01·Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids

Yeast perilipin Pet10p/Pln1p interacts with Erg6p in ergosterol metabolism

Article

作者: Ding, Yunfeng ; Zhang, Congyan ; Valachovic, Martin ; Hapala, Ivan ; Liu, Pingsheng ; Garaiova, Martina ; Holic, Roman

Lipid droplets (LD) are highly dynamic organelles specialized for the regulation of energy storage and cellular homeostasis. LD consist of a neutral lipid core surrounded by a phospholipid monolayer membrane with embedded proteins, most of which are involved in lipid homeostasis. In this study, we focused on one of the major LD proteins, sterol C24-methyltransferase, encoded by ERG6. We found that the absence of Erg6p resulted in an increased accumulation of yeast perilipin Pet10p in LD, while the disruption of PET10 was accompanied by Erg6p LD over-accumulation. An observed reciprocal enrichment of Erg6p and Pet10p in pet10Δ and erg6Δ mutants in LD, respectively, was related to specific functional changes in the LD and was not due to regulation on the expression level. The involvement of Pet10p in neutral lipid homeostasis was observed in experiments that focused on the dynamics of neutral lipid mobilization as time-dependent changes in the triacylglycerols (TAG) and steryl esters (SE) content. We found that the kinetics of SE hydrolysis was reduced in erg6Δ cells and the mobilization of SE was completely lost in mutants that lacked both Erg6p and Pet10p. In addition, we observed that decreased levels of SE in erg6Δpet10Δ was linked to an overexpression of steryl ester hydrolase Yeh1p. Lipid analysis of erg6Δpet10Δ showed that PET10 deletion altered the composition of ergosterol intermediates which had accumulated in erg6Δ. In conclusion, yeast perilipin Pet10p functionally interacts with Erg6p during the metabolism of ergosterol.