Voriconazole is a second-generation, broad-spectrum triazole antifungal. It is a derivative of fluconazole with increased antifungal activity and specificity. It is structurally related to fluconazole with a fluoropyrimidine grouping in place of a triazole moiety. It has an activity spectrum comparable to itraconazole. Voriconazole inhibits ergosterol synthesis, which is the major sterol in fungal cell membranes. The compound has fungistatic activity against yeasts (ie Candida species) and fungicidal activity against molds (ie Aspergillus species). Voriconazole was patented in 1990 by Pfizer Ireland Pharmaceutical (Ringaskiddy, Ireland).
Voriconazole is soluble in methanol and acetonitrile.
| Mechanism of Action | The mechanism of action of the azole family is to inhibit cytochrome P450 (specifically CYP450-dependent 14-alpha-sterol demethylase) which depletes ergosterol in fungal cell membranes. This increases cell permeability and disrupts normal cellular function. This can lead to growth inhibition of death, depending on the organism. |
| Spectrum | Voriconazole is fungistatic against all Candida species, including fluconazole-resistant strains of C. albicans. It is fungicidal against molds including many Aspergillus species. Voriconazole demonstrated low MICs for all Aspergillus spp. tested but appeared to be most active against Aspergillus fumigatus. |
| Microbiology Applications | Voriconazole is used as a control and ERG11 inhibitor in YPD medium. It can also be used to test its interactions with valproic acid (VPA) during VPA-synergy assessment (Chaillot et al, 2017). The main mechanisms of resistance to the triazole antifungal agents include ergosterol biosynthesis pathway modification, changes in gene expression, and increased expression of efflux pumps through various genes. |
| Eukaryotic Cell Culture Applications | Human osteoblasts were exposed in vitro to voriconazole (15 or 200 μg/ml) to review effects on cell proliferation and osteogenic differentiation. Study was undertakento learn about Periostitis, which is bony pain and diffuse periosteal ossification, has been increasingly reported with prolonged clinical use of voriconazole. Researchers found Voriconazole can induce osteoblast proliferation and enhance osteogenic activity in vitro (Allen et al, 2015). |
| Insect Biology Applications | Voriconazole can be used in an invertebrate in vitro model with Galleria mellonella (greater wax moth) larva. It is an alternative animal model for studying antifungal efficacy on mycosis, including cryptococcosis. Using 12 Cryptococcus neoformans and C. gattii strains to assess capsule thickness, biofilm formation, survival, and morbidity. The compound was found to reduce fungal burden and dissemination in the larval tissue (de Castro et al, 2019). |
| Molecular Formula | C16H14F3N5O |
| References |
Allen KC, Sanchez CJ, Niece KL, Wenke JC, Akers KS 2015. Voriconazole Enhances the Osteogenic Activity of Human Osteoblasts In Vitro through a Fluoride-Independent Mechanism. Antimicrob Agents Chemother 59(12) doi 10.1128. Beredaki M et al (2019) Voriconazole efficacy against Candida glabrata and Candida krusei: Preclinical data using a validated in vitro pharmacokinetic/pharmacodynamic model. J. Antimicrob. Chemother. 75(1):140-148 (Epub) PMID 31665417 Chaillot J et al (2017) pH-Dependant antifungal activity of Valproic acid against the human fungal pathogen Candida albicans. Frontiers in Microbiol. 8(1956):1-10 PMID 29062309 de Castro SC et al (2019) Efficacy of Voriconazole in vitro and in invertebrate model of cryptococcosis. Arch Microbiol. doi: 10.1007 (epub) PMID 31832690 Johnson LB and Kauffman CA (2003). Voriconazole: A new triazole antifungal agent. Clin. Infect. Dis. 36(5): 630-637 Lei j, Wu J and Wang T (2018) In vitro susceptibility of Candida spp. to fluconazole, itraconazole and voriconazole and the correlation between triazoles susceptibility:Results from a five-year study. J. Mycol. Med. 28(2):310-313. Richie DL et al (2013) Identification and evaluation of novel acetolactate synthase inhibitors as antifungal agents. Antimicrob. Agents Chemother. 57(5):2272-2280 PMID 23478965 Siopi M et al (2014) Susceptibility breakpoints and target values for therapeutic drug monitoring of Voriconazole and Aspergillus fumigatus in an in vitro pharmacokinetic/pharmacodynamic model. J. Antimicrob. Chemother. 69(6):1611-1619 PMID 24550381 Scott LJ and Simpson D (2007) Voriconazole: A review of its use in the management of invasive fungal infections. Drugs 67(2):269-298 PMID 17284090 |