Mechanism of Action of Antifungal Drugs
Antifungal drugs are the agents that kill or stop fungal growth and are applied to treat or prevent fungal infections(mycoses). A proper antifungal drug selectively eliminates fungal pathogens from a host with minimal toxicity to the host.
The efficiency of antifungal drugs lagged due to the cellular structure of fungi. Antibiotics work well in bacteria because they are prokaryotes with many different structural and metabolic targets. Fungi are eukaryotes, so the toxic agents of fungi are also harmful to the host. In addition, the fungi grow slowly, and most are multicellular, which makes them difficult to quantify.
However, the mechanism of action of most antifungal drugs is targeting ergosterol, an essential component of the fungal cell membrane. Instead of ergosterol, the mammalian cell membrane possesses cholesterol. Advances have been made to develop new antifungal agents and to understand the existing ones.
- Fungistatic agent: The agent that inhibits fungi’s growth and reproduction but does not necessarily kill them is called a fungistatic agent. The fungal growth resumes when such agent is removed from the environment.
- Fungicidal agent: The agent that kills fungi is called a fungicide agent.
Chemical Classification and Mechanism of Action of Antifungal Drugs
Antifungals can be grouped into various classes based on their chemical composition and the site of action.
These contain alternating conjugated double bonds that constitute a part of their macrolide ring structure. Polyenes are derived from Streptomyces species; these are broad-spectrum and fungicide drugs. These drugs act directly on the fungal cell membrane by interacting with ergosterol. Amphotericin, nystatin, and pimaricin are major drugs in this category.
- Amphotericin B combines and gets inserted within a cell membrane. It leads to the formation of micropore that causes the leakage of cellular components, and ultimately the cell dies. However, it is associated with numerous side effects. Adverse effects, like suppression of glomerular filtration, can be reduced, especially by administrating sodium chloride.
- Nystatin and pimaricin (natamycin) follow the exact mechanism of action as polyenes. Like polyenes, these are also toxic to the host, hence limited to topical use.
Drugs of this group have five-membered organic rings that contain two or three nitrogen molecules (the imidazole and the triazoles, respectively). These are fungistatic and broad-spectrum drugs.
Drugs like fluconazole, itraconazole, posaconazole, and voriconazole belong to the Triazoles, whereas cotrimoxazole, ketoconazole, econazole, and miconazole belong to the Imidazole class.
Azoles inhibit cytochrome P450 – dependent enzymes (particularly C14-demethylase). These enzymes help in the biosynthesis of ergosterol. Hence this drug inhibits fungal cell growth.
Allylamine and Morpholine
Allylamines like naftifine and terbinafine inhibit ergosterol biosynthesis at the level of squalor epoxidase. These are the structural analog of squalene. The accumulation of unsaturated hydrocarbons reduces ergosterol concentration in the fungal cell membrane leading to cell death. The morpholine drug amorolfine inhibits the same pathway at a later step.
5-Fluorocytosine or flucytosine is the fluorine analog of cytosine. It is a narrow-spectrum drug and acts as an inhibitor of DNA and RNA synthesis via the intracytoplasmic conversion of 5-fluorocytosine to 5-fluorouracil. It is subsequently converted to 5-fluoro-deoxy uridylic acid monophosphate. This non-competitive inhibitor of thymidylate synthetase then interferes with fungal nucleic acid synthesis. Hence, metabolic activities incorporate these drugs into fungal DNA and RNA and disrupt nucleic acid and protein synthesis.
Heterocyclic benzofurans like griseofulvin also act against fungal infections, especially dermatophytes. Griseofulvin is the metabolic by-product of Penicillium griseofulvum. Such drugs are fungistatic and interfere with mitosis.
These are ineffective against Candida albicans and do not disturb normal gut bacterial flora.
Echinocandins inhibit the synthesis of fungal cell wall polysaccharides- a new mode of action. It interferes with synthesizing the beta-1,3-D-glucan polymer in the fungal cell wall and results in the loss of rigidity leading the fungal cell disruption, cellular osmotic instability, and cell death. It is usually applied against Candida species.
Sordarins, a new class of antifungal drugs, inhibit fungal protein synthesis. Topical antifungals, like, ciclopirox, inhibit the transport of essential elements in the fungal cell; this disrupts DNA, RNA, and protein synthesis. These drugs are active against dermatophytes and Candida species.
Tolnaftate distorts hyphae and stunts mycelial growth in susceptible fungi.
Drawbacks of Using Antifungal Drugs
- Side Effects
Antifungal side effects vary depending on the drug type, strength/dose, and the type of pathogenic fungus. Allergy, skin reactions, liver damage, anaphylaxis, and nephrotoxicity are major side effects.
Due to the host toxicity, antifungal drugs are used in limit.
- Antifungal drug resistance
After the treatment of fungal diseases, some clear up within a few weeks, whereas some need months. Drug resistance may arise if the proper dose and period of drugs are not considered. Most antifungal drug resistance occurs because of the extended period or incomplete use of drugs or receiving too low doses. As a result, fungus no longer responds to treatment.
Mechanisms of antifungal drug resistance can be alteration in the drug target, alteration in sterol biosynthesis, reduction in intracellular concentration of target enzyme, and overexpression of the antifungal drug target.
- Denver et al. (2011). Hugo and Russell’s Pharmaceutical Microbiology. 8th edition. A John Wiley & Sons, Ltd. Publication. Page no. 191-193.
- Dixon DM & Walsh TJ (1996). Antifungal Agents. In: Baron A, editor. Medical Microbiology. Galveston (TX): The University of Texas Medical Branch at Galveston. 4th edition. Chapter 76. https://www.ncbi.nlm.nih.gov/books/NBK8263/
- Ghannoum MA & Rice LB(1999). Antifungal Agents: Mode of Action, Mechanisms of Resistance, and Correlation of These Mechanisms with Bacterial Resistance. Clin Microbiol Rev. DOI 10.1128/cmr.12.4.501 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC88922/
- Neofytos et al. (2009). Pharmacology of infections. In Pharmacology and Therapeutics. https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/systemic-antifungal-agent
- Odds, F., Brown, A., & Gow, N. (2003). Antifungal agents: mechanisms of action. Trends In Microbiology, 11(6), 272-279. https://doi.org/10.1016/s0966-842x(03)00117-3
- Martinez-Rossi, N., Peres, N., & Rossi, A. (2008). Antifungal Resistance Mechanisms in Dermatophytes. Mycopathologia, 166(5-6), 369-383. https://doi.org/10.1007/s11046-008-9110-7