AMPHOTERICIN B: A CELL MEMBRANE INHIBITOR

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The cytoplasmic membrane of fungal cell is vital to the sustenance and development of the fungal organism because this part of the cell helps to maintain a constant internal environment and it also help to regulate the inflow and outflow of materials from the cell. Antifungal agents that interfere with the synthesis of fungal cytoplasmic membrane include amphotericin B and nystatin. Drugs that perform this vital function are generally known as polyenes. Amphotericin B is a mycosamine-containing heptaene polyene antibiotic produced by Streptomyces nodosus. It is active against a wide range of pathogenic fungi and certain pathogenic protozoa. Amphotericin B is administered orally for the treatment of various mycoses, including systemic infections, but its clinical use is limited by its nephrotoxicity. Amphotericin B (Figure 1) is a widely used polyene that is naturally produced by Streptomyces species (particularly S. nodosus). Both amphotericin B and nystatin (an analogous polyene) disrupt the structural integrity of fungal cytoplasmic membrane. Nystatin is also synthesized naturally by Streptomyces species.   

Figure 1. Chemical structure of amphotericin B, a polyene antibiotic produced by Streptomyces nodosus. Photo courtesy: https://www.microbiologyclass.com

CLINICAL APPLICATION OF AMPHOTERICIN B

Amphotericin B is an intravenous antifungal agent which is clinically used to treat systemic mycosis. It has a broad spectrum of activity and it is clinically used to treat infections caused by Coccidioides species, Histoplasma species and Blastomycosis species that cause endemic or deep mycoses. Nystatin is a topical antifungal agent used topically to treat some pathogenic yeast infections especially those caused by Candida species. Nystatin is also applied at the vaginal area and on the skin surfaces to control the multiplication of yeast cells (e.g., Candida) in those regions. Amphotericin B is also used in combination with 5-FC to treat some systemic mycoses; and such antimicrobial combinations achieves a synergistic antifungal effect in the users.  

MECHANISM OF ACTION OF AMPHOTERICIN B

The polyenes (inclusive of amphotericin B and nystatin) are antifungal agents with strong affinity for fungal sterol (i.e., ergosterol), and they generally disrupt the cell membrane of pathogenic fungi. While amphotericin B is administered intravenously (IV), nystatin is mainly available as creams or solutions and is used for topical treatment of fungal infections because of their toxicity which limits their usage for systemic administration. The binding of the cell membrane of fungi by the polyenes (i.e., amphotericin B and nystatin) leads to the formation of channels or holes on the cytoplasmic membranes through which important cell molecules exit the target fungal cell. Amphotericin B and nystatin are fungicidal in action since their antimicrobial effect can lead to the death of the fungal organism.     

SIDE EFFECTS AND FUNGAL RESISTANCE TO AMPHOTERICIN B

Polyenes (inclusive of nystatin and amphotericin B) have untoward effects on human host cells upon usage. Nystatin is the most toxic and this limits its use to topical applications in the form of antifungal creams or solutions. Fever, chills, headache and dyspnea are some of the untoward effects of amphotericin B administration. Their toxicity is also extended to the renal system causing nephrotoxicity, but this can be controlled when amphotericin B is co-administered with a lipid carrier such as liposomes. The development of resistance to the polyenes by pathogenic fungi 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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