KETOCONAZOLE AND THE AZOLES: AN INHIBITOR OF ERGOSTEROL BIOSYNTHESIS IN PATHOGENIC FUNGI

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Antifungal agents that inhibit the biosynthesis of ergosterol (fungal sterol), a major component of fungal cell wall are generally known as azoles. This class of antifungal agents is called azoles because they contain the imidazole group from which other agents in this category are chemically derived. And typical examples of antifungal agents that are azoles include fluconazole, ketoconazole, itraconazole, miconazole, voriconazole and clotrimazole. A handful of the azoles or imidazoles as they are often called are used topically as antimicrobial creams or solutions to treat superficial mycoses while the others are either used orally (e.g., ketoconazole) or intravenously (e.g., fluconazole) to treat a wide variety of human mycoses inclusive of superficial mycoses, cutaneous mycoses and systemic mycoses. This group of antimicrobial agent known as azoles or imidazoles also contains agents that have activity against non-fungal organisms such as helminthes (e.g., mebendazole), parasites or protozoa (e.g., metronidazole) and pathogenic bacteria (e.g., metronidazole).     

CLINICAL APPLICATION OF KETOCONAZOLE

Ketoconazole (Figure 1) is an oral antifungal agent used to treat pathogenic yeast infections and mycoses caused by pathogenic dimorphic fungi and Cryptococcus species. They are effective for treating candidiasis, dermatophytosis and some systemic mycoses. Fluconazole is administered orally and/or intravenously; and it is used to treat mycoses caused by pathogenic Candida species, Cryptococcus species and dimorphic fungi. Itraconazole is administered orally and intravenously; and it is used to treat systemic mycosis including fungal infections caused by dimorphic fungi and invasive moulds such as Aspergillus species. Miconazole is a topical antifungal agent used to treat infections caused by Candida and other pathogenic yeasts. Voriconazole is administered orally and intravenously; and it is also used to treat fungal infections caused by Candida and other pathogenic yeasts. Clotrimazole like miconazole is mainly used topically to treat mycoses caused by Candida and pathogenic other yeasts.

Figure 1. Chemical structure of ketoconazole, an azole antifungal agent. Photo courtesy: https://www.microbiologyclass.com

MECHANISM OF ACTION OF KETOCONAZOLE

The azoles or imidazole inhibit the biosynthesis of ergosterol in fungal cell membrane by blocking the activities of cytochrome enzyme or P-450 demethylase which controls an important precursor (particularly cytochrome P-450-dependent demethylation of lanosterol) in fungal cell membrane development. Cytochrome P-450 enzyme is responsible for converting lanosterol to fungal sterol or ergosterol which is an essential component of the cytoplasmic membrane of fungi. By interfering with the cellular and metabolic synthesis of ergosterol in the fungi, the azoles disrupt the integrity of the fungal cell membrane, and this makes the cell to be more permeable to harmful substances including drugs that destroys it. Azoles have a broad spectrum of antimicrobial activity, and they are both fungicidal and fungistatic in action.

SIDE EFFECTS AND FUNGAL RESISTANCE TO KETOCONAZOLE

The azoles like other antifungal agents have some untoward effects when used for the treatment of human mycoses. Mammalian cells also contain cytochrome P-450 enzymes, and the use of imidazoles interferes with the activities of these enzymes in human cells. Cytochrome P-450 enzyme in human cells is a microsomal enzyme or haemoprotein that help in the oxidation of drugs in the liver and other human tissues. Azoles inhibit the conversion of lanosterol to cholesterol (human sterol) in human cells the same way they inhibit ergosterol biosynthesis in fungi; and they may also interfere with the synthesis of the male sex hormone (e.g., testosterone). The inhibition of mammalian cytochrome P-450 enzymes results in the interference of biosynthesis of cortisone, oestrogen and androgen, and this may lead to infertility in human hosts. The resistance of pathogenic fungi to the antimicrobial onslaught of the azoles or imidazoles is rare. 

Further reading

Anaissie E.J, McGinnis M.R, Pfaller M.A (2009). Clinical Mycology. 2nd ed. Philadelphia, PA: Churchill Livingstone Elsevier. London.

Baumgardner D.J (2012). Soil-related bacterial and fungal infections. J Am Board Fam Med, 25:734-744.

Calderone R.A and Cihlar R.L (eds). Fungal Pathogenesis: Principles and Clinical Applications. New York: Marcel Dekker; 2002.

Champoux J.J, Neidhardt F.C, Drew W.L and Plorde J.J (2004). Sherris Medical Microbiology: An Introduction to Infectious Diseases. 4th edition. McGraw Hill Companies Inc, USA.       

Gladwin M and Trattler B (2006). Clinical Microbiology Made Ridiculously Simple. 3rd edition. MedMaster, Inc., Miami, USA.

Larone D.H (2011). Medically Important Fungi: A Guide to Identification. Fifth edition. American Society of Microbiology Press, USA.

Madigan M.T., Martinko J.M., Dunlap P.V and Clark D.P (2009). Brock Biology of Microorganisms, 12th edition. Pearson Benjamin Cummings Inc, USA.

Stephenson S.L (2010). The Kingdom Fungi: The Biology of Mushrooms, Molds and Lichens. First edition. Timber Press.

Sullivan D.J and Moran G.P (2014). Human Pathogenic Fungi: Molecular Biology and Pathogenic Mechanisms. Second edition. American Society of Microbiology Press, USA.

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