Cloning and characterization of CYP51 from Mycobacterium avium.

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Pietila MP, Vohra PK, Sanyal B, Wengenack NL, Raghavakaimal S, Thomas CF Jr

Cloning and characterization of CYP51 from Mycobacterium avium.

Am J Respir Cell Mol Biol. 2006 Aug;35(2):236-42. Epub 2006 Mar 16.

PubMed ID

16543605 [ View in PubMed

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Abstract

Mycobacterium avium complex (MAC) causes chronic lung disease in immunocompetent people and disseminated infection in patients with AIDS. MAC is intrinsically resistant to many conventional antimycobacterial agents, it develops drug resistance rapidly to macrolide antibiotics, and patients with MAC infection experience frequent relapses or the inability to completely eradicate the infection with current treatment. Treatment regimens are prolonged and complicated by drug toxicity or intolerances. We sought to identify biochemical pathways in MAC that can serve as targets for novel antimycobacterial treatment. The cytochrome P450 enzyme, CYP51, catalyzes an essential early step in sterol metabolism, removing a methyl group from lanosterol in animals and fungi, or from obtusifoliol in plants. Azoles inhibit CYP51 function, leading to an accumulation of methylated sterol precursors. This perturbation of normal sterol metabolism compromises cell membrane integrity, resulting in growth inhibition or cell death. We have cloned and characterized a CYP51 from MAC that functions as a lanosterol 14alpha-demethylase. We show the direct interactions of azoles with purified MAC-CYP51 by absorbance and electron paramagnetic resonance spectroscopy, and determine the minimum inhibitory concentrations (MICs) of econazole, ketoconazole, itraconazole, fluconazole, and voriconazole against MAC. Furthermore, we demonstrate that econazole has a MIC of 4 mug/ml and a minimum bacteriocidal concentration of 4 mug/ml, whereas ketoconazole has a MIC of 8 mug/ml and a minimum bacteriocidal concentration of 16 mug/ml. Itraconazole, voriconazole, and fluconazole did not inhibit MAC growth to any significant extent.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Econazole	Cytochrome P450 51	Protein	Yeast	Yes	Antagonist	Details