Biomaterial Database

In vitro efficacy of the combination of voriconazole and anidulafungin against voriconazole-resistant cyp51A mutants of Aspergillus fumigatus. 2012

Suganthini Krishnan-Natesan, and Wenjuan Wu, and Pranatharthi H Chandrasekar

Wayne State University, Detroit, MI, USA. skrishn@med.wayne.edu

We selected voriconazole-resistant (VCZ-R) Aspergillus fumigatus in the laboratory, characterized the cyp51A gene for possible mutations and evaluated the in vitro activities of voriconazole and anidulafungin alone and in combination against VCZ-R isolates of A. fumigatus using a fractional inhibitory concentration index (FICI) methodology. Voriconazole-resistant isolates were selected from wild-type A. fumigatus isolates in the laboratory by a 2-step selection process (plus 1 clinical isolate). The MICs of azoles (VCZ, posaconazole, itraconazole) and echinocandins (anidulafungin, micafungin, and caspofungin) for all A. fumigatus isolates were then determined in RPMI1640 using the broth microdilution technique recommended by the Clinical Laboratory and Standards Institute M38-A2 methodology and the FICI calculated. The combination of VCZ and anidulafungin was synergistic (FICI <0.5) not only against VCZ-susceptible isolates, but also against 8 of 10 VCZ-R, G448S mutants of A. fumigatus. The combination demonstrated synergy against the VCZ-R clinical isolate as well.

UI	MeSH Term	Description	Entries
D008826	Microbial Sensitivity Tests	Any tests that demonstrate the relative efficacy of different chemotherapeutic agents against specific microorganisms (i.e., bacteria, fungi, viruses).	Bacterial Sensitivity Tests,Drug Sensitivity Assay, Microbial,Minimum Inhibitory Concentration,Antibacterial Susceptibility Breakpoint Determination,Antibiogram,Antimicrobial Susceptibility Breakpoint Determination,Bacterial Sensitivity Test,Breakpoint Determination, Antibacterial Susceptibility,Breakpoint Determination, Antimicrobial Susceptibility,Fungal Drug Sensitivity Tests,Fungus Drug Sensitivity Tests,Sensitivity Test, Bacterial,Sensitivity Tests, Bacterial,Test, Bacterial Sensitivity,Tests, Bacterial Sensitivity,Viral Drug Sensitivity Tests,Virus Drug Sensitivity Tests,Antibiograms,Concentration, Minimum Inhibitory,Concentrations, Minimum Inhibitory,Inhibitory Concentration, Minimum,Inhibitory Concentrations, Minimum,Microbial Sensitivity Test,Minimum Inhibitory Concentrations,Sensitivity Test, Microbial,Sensitivity Tests, Microbial,Test, Microbial Sensitivity,Tests, Microbial Sensitivity
D011743	Pyrimidines	A family of 6-membered heterocyclic compounds occurring in nature in a wide variety of forms. They include several nucleic acid constituents (CYTOSINE; THYMINE; and URACIL) and form the basic structure of the barbiturates.
D003577	Cytochrome P-450 Enzyme System	A superfamily of hundreds of closely related HEMEPROTEINS found throughout the phylogenetic spectrum, from animals, plants, fungi, to bacteria. They include numerous complex monooxygenases (MIXED FUNCTION OXYGENASES). In animals, these P-450 enzymes serve two major functions: (1) biosynthesis of steroids, fatty acids, and bile acids; (2) metabolism of endogenous and a wide variety of exogenous substrates, such as toxins and drugs (BIOTRANSFORMATION). They are classified, according to their sequence similarities rather than functions, into CYP gene families (>40% homology) and subfamilies (>59% homology). For example, enzymes from the CYP1, CYP2, and CYP3 gene families are responsible for most drug metabolism.	Cytochrome P-450,Cytochrome P-450 Enzyme,Cytochrome P-450-Dependent Monooxygenase,P-450 Enzyme,P450 Enzyme,CYP450 Family,CYP450 Superfamily,Cytochrome P-450 Enzymes,Cytochrome P-450 Families,Cytochrome P-450 Monooxygenase,Cytochrome P-450 Oxygenase,Cytochrome P-450 Superfamily,Cytochrome P450,Cytochrome P450 Superfamily,Cytochrome p450 Families,P-450 Enzymes,P450 Enzymes,Cytochrome P 450,Cytochrome P 450 Dependent Monooxygenase,Cytochrome P 450 Enzyme,Cytochrome P 450 Enzyme System,Cytochrome P 450 Enzymes,Cytochrome P 450 Families,Cytochrome P 450 Monooxygenase,Cytochrome P 450 Oxygenase,Cytochrome P 450 Superfamily,Enzyme, Cytochrome P-450,Enzyme, P-450,Enzyme, P450,Enzymes, Cytochrome P-450,Enzymes, P-450,Enzymes, P450,Monooxygenase, Cytochrome P-450,Monooxygenase, Cytochrome P-450-Dependent,P 450 Enzyme,P 450 Enzymes,P-450 Enzyme, Cytochrome,P-450 Enzymes, Cytochrome,Superfamily, CYP450,Superfamily, Cytochrome P-450,Superfamily, Cytochrome P450
D004357	Drug Synergism	The action of a drug in promoting or enhancing the effectiveness of another drug.	Drug Potentiation,Drug Augmentation,Augmentation, Drug,Augmentations, Drug,Drug Augmentations,Drug Potentiations,Drug Synergisms,Potentiation, Drug,Potentiations, Drug,Synergism, Drug,Synergisms, Drug
D005656	Fungal Proteins	Proteins found in any species of fungus.	Fungal Gene Products,Fungal Gene Proteins,Fungal Peptides,Gene Products, Fungal,Yeast Proteins,Gene Proteins, Fungal,Peptides, Fungal,Proteins, Fungal
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000077612	Anidulafungin	Echinocandin antifungal agent that is used in the treatment of CANDIDEMIA and CANDIDIASIS.	1-((4R,5R)-4,5-Dihydroxy-N2-((4''-(pentyloxy)(1,1':4',1''-terphenyl)-4-yl)carbonyl)-L-ornithine)-echinocandin B,Eraxis,LY 303366,LY-303366,LY303366
D000935	Antifungal Agents	Substances that destroy fungi by suppressing their ability to grow or reproduce. They differ from FUNGICIDES, INDUSTRIAL because they defend against fungi present in human or animal tissues.	Anti-Fungal Agents,Antifungal Agent,Fungicides, Therapeutic,Antibiotics, Antifungal,Therapeutic Fungicides,Agent, Antifungal,Anti Fungal Agents,Antifungal Antibiotics
D001232	Aspergillus fumigatus	A species of imperfect fungi from which the antibiotic fumigatin is obtained. Its spores may cause respiratory infection in birds and mammals.	Aspergillus fumigates,Neosartorya fumigata,Sartorya fumigata
D014230	Triazoles	Heterocyclic compounds containing a five-membered ring with two carbon atoms and three nitrogen atoms with the molecular formula C2H3N3.	Triazole