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Pharmacology of azole antifungal agents
Published in Mahmoud A. Ghannoum, John R. Perfect, Antifungal Therapy, 2019
All azole antifungal agents share a common, primary mechanism of action, inhibition of the cytochrome P-450 dependent enzyme lanosterol 14-alpha-demethylase [3]. This enzyme is necessary for the conversion of lanosterol to ergosterol, a vital component of the cellular membrane of fungi. Disruptions in the biosynthesis of ergosterol cause significant damage to the cell membrane by increasing its permeability, resulting in cell lysis and death.
Individual conditions grouped according to the international nosology and classification of genetic skeletal disorders*
Published in Christine M Hall, Amaka C Offiah, Francesca Forzano, Mario Lituania, Michelle Fink, Deborah Krakow, Fetal and Perinatal Skeletal Dysplasias, 2012
Christine M Hall, Amaka C Offiah, Francesca Forzano, Mario Lituania, Michelle Fink, Deborah Krakow
Genetics: can be caused by heterozygous, dominant mutations in the gene FGFR2 (10q26) (type 1) or by homozygous, recessive mutations in the gene POR (7q11.2) (type 2), encoding cytochrome P450 (lanosterol 14 alpha-demethylase) oxidore-ductase (POR). The latter gene is involved in steroidogenesis and as a consequence patients with ABS type 2 can show sexual ambiguity. A phenocopy of ABS is observed in patients exposed in utero to fluconazole, an antifungal agent which inhibits lanosterol 14 alpha-demethylase.
Molecular Diagnostics: Present and Future
Published in Johan A. Maertens, Kieren A. Marr, Diagnosis of Fungal Infections, 2007
Holger Hebart, Juergen Loeffler, Hermann Einsele
The selection of a target gene followed by the design of the primers and probes are the most important issues when creating a PCR assay. In contrast to Candida spp. where a variety of PCR protocols based on single copy genes (lanosterol-14-alpha-demethylase, actin, chitin synthase) exist, the detection of mold DNA has been largely achieved by targeting multi-copy genes. More recently, Kanbe et al. described a nested PCR assay using specific primers binding to the DNA topoisomerase II gene (56). Primers targeting multi-copy genes bind to the 18S or 28S subunits of the ribosomal DNA (12,57,58) or to the highly variable intergenic transcribed spacer regions (ITS1–4) that are flanking the ribosomal gene regions (30,59,60). Furthermore, mitochondrial genes have been used for the design of primers for diagnostic assays (61). Luo et al. described a multiplex PCR with five sets of species-specific primers binding to the ITS1 and ITS2 regions. They found that this multiplex PCR method provided 100% sensitivity and specificity in testing a total of 242 fungal isolates (60).
Evolution of antifungals for invasive mold infections in immunocompromised hosts, then and now
Published in Expert Review of Anti-infective Therapy, 2023
Zoe Freeman Weiss, Jessica Little, Sarah Hammond
Azole antifungals were first granted approval by the US Food and Drug Administration (FDA) in the 1990s. Azoles work by disrupting the cytochrome P450-dependent enzyme lanosterol 14-alpha-demethylase, which converts lanosterol to ergosterol, an essential component of the fungal cell membrane. Available in both oral and parenteral formulations, the first-generation triazole, fluconazole, is highly active against many yeast species but has little activity against mold. Itraconazole was subsequently developed for both yeast and mold infections (eg. histoplasmosis, coccidioidomycosis, blastomycosis, and to a lesser extent, aspergillosis). Because the first generation of azoles are metabolized by the CYP450 system, drug interactions, prolongation of the QTC interval, and hepatotoxicity are common toxicities [7].
In silico molecular docking for assessing anti-fungal competency of hydroxychavicol, a phenolic compound of betel leaf (Piper betle L.) against COVID-19 associated maiming mycotic infections
Published in Drug Development and Industrial Pharmacy, 2022
Vinusri Sekar, Gnanam Ramasamy, Caroline Ravikumar
The mechanism of action chosen for the approved anti-fungal drugs is the interference in the ergosterol biosynthetic pathway by inhibiting the Lanosterol 14 alpha demethylase, which in turn leads to the accumulation of precursors and intermediates and reduction in membrane integrity in the lipid layers, ultimately results in cytotoxicity and inhibition of the fungal growth [55]. Hence, Lanosterol 14 alpha demethylase was chosen as a target for this study.