title: The anti-Aspergillus drug pipeline: Is the glass half full or empty?
abstract: Aspergillosis has emerged as important human mycoses, in view of the ever expanding population at risk. The emergence of resistance to the most commonly used drugs for aspergillosis, the azoles, the mediocre activity, and frequent toxicity of the current antifungal armamentarium, support the need for development of novel antifungals for treatment of this disease. In this minireview, we describe recent efforts by small drug companies and University research labs to develop novel therapies for invasive aspergillus infections. We specifically discuss four small-molecule antifungals (T-2307, E1210/APX001, ASP2397, and F901318) with novel modes-of-action, which are currently entering phase I clinical trials. In addition, we provide a nonexhaustive discussion of some interesting, yet early developments in the quest for improved therapeutic strategies such as (i) novel formulations of amphotericin B including AMB nanoparticle suspensions and AMB-arabinogalactan or AMB-PEG conjugates that show low toxicity and high efficacy in preclinical animal models, (ii) repurposed drugs that synergize with existing antifungals (clozafimine, trichostatin A, MGCD290, geldanamycin, tacrolimus, cyclosporin), (iii) natural products (psoriasin, humidimycin), and (iv) immunotherapy using adoptive transfer of activated immune cells with antifungal activity. We argue that despite the plethora of candidates, the extremely low success rates of drug development leading to clinically useful drugs reinforces the need for continued clinical reliance on mainstream antifungals and their improved derivatives.
authors: Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv Israel.
authors: Nir
authors: N
authors: Osherov
authors: Department of Infectious Diseases, Infection Control and Employee Health, University of Texas MD Anderson Cancer Center, Houston, TX, USA dkontoyi@mdanderson.org nosherov@post.tau.ac.il.
authors: Dimitrios P
authors: DP
authors: Kontoyiannis
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000302:isolation & purification* / Q000494:pharmacology*; D001228:Aspergillosis / Q000628:therapy*; D001230:Aspergillus / Q000187:drug effects* / Q000276:immunology*; D001688:Biological Products / Q000302:isolation & purification / Q000494:pharmacology; D002986:Clinical Trials as Topic; D004339:Drug Compounding; D055808:Drug Discovery / Q000639:trends*; D004353:Drug Evaluation, Preclinical; D058492:Drug Repositioning; D004358:Drug Therapy / Q000379:methods; D006801:Humans; D007167:Immunotherapy / Q000379:methods
chemical_list: D000935:Antifungal Agents; D001688:Biological Products
keywords: Antifungal drug discovery; immunotherapy; natural products