Brielle Haas RISE Spring 2015 Dr. Gullo Antifungal Therapies Brielle Haas RISE Spring 2015 Dr. Gullo

Deficits of Antifungal Therapies Antifungal Problems Growing clinical need Lack of treatment options Antifungal resistance Low efficacy of current treatments

Fungal Cell Characteristics Distinctive cell wall components Chitinases Glucanases Ergosterol Mannan Hydrolytic enzymes Growth as a filament Hyphae

Fungal Hyphae Hyphae growth Fungal Sinusitis

Growing Susceptibility Immunocompromised patients Patients with HIV/AIDS and other autoimmune disorders Patients taking certain medications Cancer Patients Chemotherapy and radiation lower immunity Organ transplant patients Anti-rejection medication lowers immunity Stem cell transplant patients Hospitalized patients

Common Invasive Fungal Infections Aspergillus spp. Aspergillosis (lung infections) Candida spp. Candidiasis (thrush and yeast infections) Cryptococcus (C. neoformans and C. gatti ) Cryptococcosis (lung infections) Cryptococcal meningitis (CNS infections) Mucoromycotina Mucoromycosis (skin, lung, and sinus infections) Pneumocystis jirovecii Pneumocystic pneumonia (PCP)

Current Antifungal Treatments Polyenes Azoles Enchinocandins Amphotericin B Fluconazole Voriconazole Posaconazole Itraconazole Caspofungin Micafungin Anidulafungin

Polyenes Amphotericin B Under development Fungicidal High toxicity (lower with lipid formulations) Targets ergosterol on cell membrane Used in combination with flucytosine Used for cryptococcal meningitis and invasive mucormycotina Under development Nystatin Amphotericin B cochleate formulation

Polyene Structures

Azoles All types Fluconazole Most broadly used class Inhibits cytochrome P-450, which is responsible for ergosterol synthesis Fungistatic,except for voriconazole May interfere with other medication Fluconazole Used against yeasts such as Candida and Cryptococcus Not active against molds Used to treat cryptococcal meningitis in resource-poor regions where Amphotericin B is not available

Azoles Voriconazole Posaconazole Itraconazole Under development Fungicidal Active against yeasts and molds Treats Aspergillus spp. infections Posaconazole Treats Mucor spp. infections Itraconazole Active against yeasts and molds Treats superficial fungal infections Under development Albaconazole Isavuconazole Ravuconazole

Azole Structures

Enchinocandins General Caspofungin Anidulafungin Micafungin Inhibit glucan synthesis Used as secondary choice treatment options for Candida and Aspergillus Caspofungin Fungicidal toward A. fumigatus Anidulafungin Used as fluconazole alternative Micafungin Used as antifungal prophylaxis after stem cell transplant Under development Aminocandin Enfumifungin

Enchinocandin Structures

Further Under Development Nikkomycin Z Inhibits chitin synthesis Sordarins Inhibits elongation factor 2 which prevents protein synthesis Nanoparticle Formations Attempt to solve toxicity and solubility issues of current treatments (Amphotericin B and Itraconazole)

Antifungal Drug Targets

Fungal CNS Infections Difficulty in diagnosis CSF screenings MRI Passage of medication through blood-brain barrier Need for surgical intervention Risks of any invasive neurological procedure Increased susceptibility to other fungal infections

Research Topics Why are there so few effective antifungal drugs? What efforts are currently being made to “fix” the problems with antifungal therapies? How do these problems manifest in the treatment of fungal infections of the CNS?

References http://mic.sgmjournals.org/content/150/7/2029.abstract http://stm.sciencemag.org/content/4/165/165rv13.abstract http://www.nature.com/nrd/journal/v9/n9/full/nrd3074.html http://jac.oxfordjournals.org/content/56/suppl_1/i5.abstract http://www.cdc.gov/fungal/ Roemer T, Krysan DJ. Antifungal drug development: challenges, unmet clinical needs, and new approaches. Cold Spring Harbor perspectives in medicine 2014;4(5):a019703. McCarthy M, Rosengart A, Schuetz AN, Kontoyiannis DP, Walsh TJ. Mold Infections of the Central Nervous System. The New England Journal of Medicine 2014;371(2):150-60.