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BIOL 4849 Lecture 6 (X11) BIOL 4849: Medical Mycology Summer 2011 Antifungal Agents and Antifungal Therapy http://www.doctorfungus.org/thedrugs/ BIOL 4849 (Summer 2011) Copyright © 2011 Chester R. Cooper, Jr. Disclaimer: This lecture slide presentation is intended solely for educational purposes. Many of the images contained herein are the property of the original owner, as indicated within the figure itself or within the figure legend. These images are used only for illustrative purposes within the context of this lecture material. Use of these images outside the purpose of this presentation may violate the rights of the original owner. Dr. Cooper and Youngstown State University assume no responsibility for the unauthorized use of the material BIOL 4849 (Summer 2011) Copyright © 2011 Chester R. Cooper, Jr. contained herein. History of Antifungals History of Antifungals (cont.) • From late 1800’s to ca. 1950, treatments for • First successful antifungal – supersaturated fungal infections consisted mainly of surgical potassium iodide (SSKI) interventions as well as several non-surgical – Oral solution for treating cutaneous sporotrichosis treatments – Limited spectrum of effectiveness – Potassium Iodide (KI) • Discovery of active and safe antifungals – Phenol – Griseofulvin (1939 by Oxford) – Dyes – Benzimidazole (1944 by Wooley) – Noxious agents such as bromine, permanganate, – Propamidine (1945 by Elson) and oil of turpentine with olive oil – Nystatin (1950 by Brown and Hazen) BIOL 4849 (Summer 2011) Copyright © 2011 Chester R. Cooper, Jr. BIOL 4849 (Summer 2011) Copyright © 2011 Chester R. Cooper, Jr. History of Antifungals (cont.) History of Antifungals (cont.) . Nystatin was the first antifungal • Propamidine and stilbamidine (and with important implications for the derivatiaves) used to treat blastomycosis treatment of fungal infections (1951) . Named new antifungal for their • Amphotericin B (discovered in 1955) used to employer: NY (New York) – Stat treat blastomycosis (State) –in Rachel Brown (left) and • IV amphotericin B developed in 1960 Elizabeth Hazen (right): co-discoverers of Nystatin . Brown and Hazen donated all • However, discovery of safe and effective (http://inventors.about.com) Nystatin royalties to academic antifungal drugs slowed over the next 30 science (> $13 million) years BIOL 4849 (Summer 2011) Copyright © 2011 Chester R. Cooper, Jr. BIOL 4849 (Summer 2011) Copyright © 2011 Chester R. Cooper, Jr. Lecture 6: Antifungal Agents 1 BIOL 4849: Medical Mycology Summer 2011 History of Antifungals (cont.) History of Antifungals (cont.) • 5-fluorocytosine (flucytosine; 5FC) – • Additional antifungals developed in 1964, was initially effective – Econazole (1974) against Candida and Cryptococcus, but – Ketoconazole (1981) resistance limited its use as monotherapy – Allylamines (1970-1980s) • 5FC now used in combination with – Lipid formulations of polyenes (1970-1980s) amphotericin B – Fluconazole and Echinocandins (1990s) • The topical agents, miconazole and • Introduction of fluconazole transformed the clotrimazole were developed in 1969 development of antifungals BIOL 4849 (Summer 2011) Copyright © 2011 Chester R. Cooper, Jr. BIOL 4849 (Summer 2011) Copyright © 2011 Chester R. Cooper, Jr. Antifungal Targets • Similarities of fungi and mammals have made the search for appropriate targets difficult • Three main targets due to differences – Plasma membrane sterols – Nucleic acid biosynthesis – Cell wall components BIOL 4849 (Summer 2011) Copyright © 2011 Chester R. Cooper, Jr. BIOL 4849 (Summer 2011) Copyright © 2011 Chester R. Cooper, Jr. BIOL 4849 (Summer 2011) Copyright © 2011 Chester R. Cooper, Jr. BIOL 4849 (Summer 2011) Copyright © 2011 Chester R. Cooper, Jr. Lecture 6: Antifungal Agents 2 BIOL 4849: Medical Mycology Summer 2011 Shapiro et al. Microbiol. Molec. Biol. Rev. 75: 213-267, 2011 Shapiro et al. Microbiol. Molec. Biol. Rev. 75: 213-267, 2011 BIOL 4849 (Summer 2011) Copyright © 2011 Chester R. Cooper, Jr. BIOL 4849 (Summer 2011) Copyright © 2011 Chester R. Cooper, Jr. Current Systemic Antifungals • Polyenes – Macrolide antibiotics containing unsaturated diene bonds – Rapidly bind to sterols, preferentially to ergosterol - ‘the’ sterol found in fungal plasma membranes – Mechanism of action: • Disruption of the osmotic integrity of the cell membrane with subsequent leakage of intracellular ions and materials • Oxidative damage of membrane components Shapiro et al. Microbiol. Molec. Biol. Rev. 75: 213-267, 2011 BIOL 4849 (Summer 2011) Copyright © 2011 Chester R. Cooper, Jr. BIOL 4849 (Summer 2011) Copyright © 2011 Chester R. Cooper, Jr. Current Systemic Antifungals (cont.) – Two drugs currently in use: • Nystatin – First true antifungal agent discovered by Brown and Hazen (1948) – Secondary metabolite from the actinomycete Streptomyces noursei – Highly insoluble and toxic as a systemic drug – Used as a topical agent Antifungal agents Nystatin and Amphotericin B. Source: www.doctorfungus.com BIOL 4849 (Summer 2011) Copyright © 2011 Chester R. Cooper, Jr. BIOL 4849 (Summer 2011) Copyright © 2011 Chester R. Cooper, Jr. Lecture 6: Antifungal Agents 3 BIOL 4849: Medical Mycology Summer 2011 Current Systemic Antifungals (cont.) Current Systemic Antifungals (cont.) • Amphotericin B – Mechanism of resistance (amphotericin B) – Largely insoluble; often used as a • Reduced membrane ergosterol due to defective deoxycholate suspension or in lipid vesicles biosynthetic genes – Tolerated much better than nystatin, but still • Alterations in sterol content or structure toxic at high levels • Masking of ergosterol molecules – Can cause renal failure, suppression of erythropoietin, and anemia – Effective against a broad spectrum of fungi; few are innately resistant – Resistance can be acquired BIOL 4849 (Summer 2011) Copyright © 2011 Chester R. Cooper, Jr. BIOL 4849 (Summer 2011) Copyright © 2011 Chester R. Cooper, Jr. Current Systemic Antifungals (cont.) • Flucytosine (5-fluorocytosine) – Only antimetabolite of its type known to be effective against fungal infections – Mechanism of action: activated via deamination by fungal cells to produce 5-fluorouracil, a known inhibitor of DNA and protein synthesis (via formation of aberrant RNA) – Highly water soluble; used as an oral or Flucytosine. Source: www.doctorfungus.com intravenous agent – Fairly well tolerated but can cause bone marrow depression and gastrointestinal distress BIOL 4849 (Summer 2011) Copyright © 2011 Chester R. Cooper, Jr. BIOL 4849 (Summer 2011) Copyright © 2011 Chester R. Cooper, Jr. Current Systemic Antifungals (cont.) Current Systemic Antifungals (cont.) – Narrow spectrum agent against • Azoles • Candidiasis – Mechanism of action: all work by inhibition of the • Cryptococcosis fungal cytochrome 14α-demethylase, an enzyme critical in the biosynthesis of ergosterol • Aspergillosis (minimally effective) • Causes same type of damage that occurs with • Chromoblastomycosis polyene treatment (loss of membrane integrity) – Resistance is common due to mutations in • May take several generations to show affect • Plasma membrane cytosine permease, or – Types of azoles • Deaminase • Triazoles: fluconazole, voriconazole – Often used in combination with amphotericin B • Imidazoles: ketoconazole, itraconazole, posaconazole BIOL 4849 (Summer 2011) Copyright © 2011 Chester R. Cooper, Jr. BIOL 4849 (Summer 2011) Copyright © 2011 Chester R. Cooper, Jr. Lecture 6: Antifungal Agents 4 BIOL 4849: Medical Mycology Summer 2011 Current Systemic Antifungals (cont.) – Generally considered to be fungistatic, as opposed fungicidal, agents – Fluconazole, compared to the other azoles, is highly soluble in water; other agents typically require a carrier agent (e.g., cyclodextrin) for systemic or oral use – Mechanisms of resistance may include: • Alteration in demethylase • Overexpression of demethylase • Overexpression of efflux systems • Changes in membrane ergosterol composition BIOL 4849 (Summer 2011) Copyright © 2011 Chester R. Cooper, Jr. BIOL 4849 (Summer 2011) Copyright © 2011 Chester R. Cooper, Jr. Current Systemic Antifungals (cont.) • Echinocandins – Cyclic glycopeptides that inhibit fungal 1,3-β- glucan synthesis (cell wall component) – Best used intravenously – Great potency against: • Candidiasis - fungicidal • Aspergillosis -fungistatic – Cases of cryptococcosis are resistant because Cryptococcus contains 1,6-β-glucans – Echinocandins include cilofungin, caspofungin, micafungin, and anidulafungin BIOL 4849 (Summer 2011) Copyright © 2011 Chester R. Cooper, Jr. BIOL 4849 (Summer 2011) Copyright © 2011 Chester R. Cooper, Jr. Current Systemic Antifungals (cont.) Superficial Antifungal Agents • Nikkomycins • A number of very effective drugs have been – Inhibitors of chitin synthesis developed to treat fungal infections, but are • Good in vivo activity against used as topical agents due to their insolubility coccidioidomycosis and blastomycosis or toxicity • Moderate activity against candidiasis, • Allylamines histoplasmosis, and cryptococcosis – Include butenafine, naftifine, and terbinafine – Exhibits synergistic activity with fluconazole and – Mechanism of action: inhibits squalene epoxidase, echinocandins an enzyme important in membrane biosynthesis • Griseofulvin (squalene accumulation is toxic) – Microtubule inhibitor (quit toxic); fungicidal – Used to treat candidiasis and dermatomycosis – Treats dermatomycosis and candidiasis BIOL 4849 (Summer 2011) Copyright © 2011 Chester R. Cooper, Jr. BIOL 4849 (Summer 2011) Copyright © 2011 Chester R. Cooper, Jr. Lecture 6: Antifungal Agents
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