NUCLEIC ACID SYNTHESIS INHIBITORS (Flucytosine or 5-fluorocytosine)

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Some fungal agents are classified as nucleic acid inhibitors because they interfere with the biosynthesis of DNA and RNA which are both critical 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 (DNA and RNA) 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; and 5-FC inhibits the synthesis of nucleic acids (DNA and RNA) and protein synthesis in fungal cells.

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

CLINICAL APPLICATION OF 5-FLUOROCYTOSINE (5-FC)

Flucytosine is rapidly and virtually completely absorbed following oral administration. It has in vitro and in vivo activity against Candida and Cryptococcus. Flucytosine (5-FC) is clinically used for the treatment of systemic mycoses. 5-FC 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 5-FC is deaminated or converted to 5-fluorouracil (a false nucleotide) by cytosine deaminase in the target 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 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. Pathogenic fungi develop resistance to the agent especially in cases where the drug is used alone. Mutation in the target pathogenic fungi could also lead to resistance of the organism to the antifungal agent.   

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, USA.

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