FLUCYTOSINE OR 5-FLUOROCYTOSINE (5-FC): A NUCLEIC ACID SYNTHESIS INHIBITOR

Some fungal agents are classified as nucleic acid inhibitors because they interfere with the biosynthesis of DNA and RNA which are both important for the overall development of the target pathogenic fungi. Flucytosine or 5-fluorocytosine is a typical example of antifungal agent that inhibits the synthesis of nucleic acids in pathogenic fungi. Flucytosine or 5-fluorocytosine (5-FC) is a synthetic antifungal agent that is used for the treatment of some fungal infections. Flucytosine (Figure 1) is an oral antifungal agent that acts as an antimetabolite. The drug is an analogue of cytosine. 5-FC inhibits the synthesis of nucleic acids (DNA and RNA) and protein synthesis in fungal cells.

Figure 1. Chemical structure of 5-fluorocytosine (5-FC). Photo courtesy: https://www.microbiologyclass.com

CLINICAL APPLICATION OF 5-FLUOROCYTOSINE

Flucytosine is rapidly and virtually completely absorbed following oral administration. It has in vitro and in vivo activity against Candida species and Cryptococcus species. Flucytosine (5-FC) is clinically used for the treatment of systemic mycoses, and the agent is active against Candida species including C. albicans and Cryptococcus neoformans that cause candidiasis and cryptococcosis respectively. It is usually used in combination with other antifungal agents (e.g., amphotericin B) for treating deep or systemic mycoses. Flucytosine is mainly used for treating yeast infections, and the drug has little or no activity against dimorphic fungi and moulds.

MECHANISM OF ACTION OF 5-FLUOROCYTOSINE

Flucytosine is a nucleoside analogue of cytosine; and that is why it is often regarded as an antimetabolite. Upon administration, 5-FC is deaminated or converted to 5-fluorouracil (a false nucleotide) by cytosine deaminase in the target pathogenic fungi. The formation of 5-fluorouracil and its incorporation by the pathogenic fungi inhibits the activity of thymidylate synthetase, which is the enzyme that directs DNA synthesis in the organism. Interference of the activities of thymidylate synthetase limits the supply of nucleotides (e.g., thymidine) which is required for the synthesis of DNA in fungi. Flucytosine is a narrow spectrum antifungal agent, and it is only used to treat human mycoses caused by pathogenic yeasts especially in systemic fungal infections.     

SIDE EFFECTS AND FUNGAL RESISTANCE TO 5-FLUOROCYTOSINE

The clinical usage of flucytosine causes the depression of bone marrow development in recipient hosts. This can impact negatively on the immune system of the recipient patient. Pathogenic fungi also develop resistance to flucytosine especially in cases where the drug is used alone.  

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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