INHIBITORS OF ERGOSTEROL BIOSYNTHESIS

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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 because they contain the imidazole group from which other antifungal agents in this category are chemically derived  from. 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 antifungal agents that have antimicrobial activity against non-fungal organisms such as helminthes (e.g., mebendazole), parasites or protozoa (e.g., metronidazole) and pathogenic bacteria (e.g., metronidazole).     

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CLINICAL APPLICATION OF THE AZOLES

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

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

MECHANISM OF ACTION OF THE AZOLES

The azoles or imidazoles 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. 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 THE AZOLES

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. 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

Ashutosh Kar (2008). Pharmaceutical Microbiology, 1st edition. New Age International Publishers: New Delhi, India. 

Block S.S (2001). Disinfection, sterilization and preservation. 5th edition. Lippincott Williams & Wilkins, Philadelphia and London.

Courvalin P, Leclercq R and Rice L.B (2010). Antibiogram. ESKA Publishing, ASM Press, Canada.

Denyer S.P., Hodges N.A and Gorman S.P (2004). Hugo & Russell’s Pharmaceutical Microbiology. 7th ed. Blackwell Publishing Company, USA. Pp.152-172.

Ejikeugwu Chika, Iroha Ifeanyichukwu, Adikwu Michael and Esimone Charles (2013). Susceptibility and Detection of Extended Spectrum β-Lactamase Enzymes from Otitis Media Pathogens. American Journal of Infectious Diseases. 9(1):24-29.

Finch R.G, Greenwood D, Norrby R and Whitley R (2002). Antibiotic and chemotherapy, 8th edition. Churchill Livingstone, London and Edinburg. Russell A.D and Chopra I (1996). Understanding antibacterial action and resistance. 2nd edition. Ellis Horwood Publishers, New York

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