Acylhydrazones as Antifungal Agents Targeting the Synthesis of Fungal Sphingolipids

Author:

Lazzarini Cristina12,Haranahalli Krupanandan3,Rieger Robert4,Ananthula Hari Krishna5,Desai Pankaj B.5,Ashbaugh Alan6,Linke Michael J.67,Cushion Melanie T.67,Ruzsicska Bela3,Haley John34,Ojima Iwao38,Del Poeta Maurizio1239

Affiliation:

1. Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York, USA

2. Veterans Administration Medical Center, Northport, New York, USA

3. Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, New York, USA

4. Proteomics Center, Stony Brook University, Stony Brook, New York, USA

5. Department of Pharmaceutical Sciences, University of Cincinnati, Cincinnati, Ohio, USA

6. Department of Veterans Affairs Medical Center, Cincinnati, Ohio, USA

7. University of Cincinnati College of Medicine, Cincinnati, Ohio, USA

8. Department of Chemistry, Stony Brook University, Stony Brook, New York, USA

9. Division of Infectious Diseases, School of Medicine, Stony Brook University, Stony Brook, New York, USA

Abstract

ABSTRACT The incidence of invasive fungal infections has risen dramatically in recent decades. Current antifungal drugs are either toxic, likely to interact with other drugs, have a narrow spectrum of activity, or induce fungal resistance. Hence, there is a great need for new antifungals, possibly with novel mechanisms of action. Previously our group reported an acylhydrazone called BHBM that targeted the sphingolipid pathway and showed strong antifungal activity against several fungi. In this study, we screened 19 derivatives of BHBM. Three out of 19 derivatives were highly active against Cryptococcus neoformans in vitro and had low toxicity in mammalian cells. In particular, one of them, called D13, had a high selectivity index and showed better activity in an animal model of cryptococcosis, candidiasis, and pulmonary aspergillosis. D13 also displayed suitable pharmacokinetic properties and was able to pass through the blood-brain barrier. These results suggest that acylhydrazones are promising molecules for the research and development of new antifungal agents.

Funder

HHS | NIH | National Institute of Allergy and Infectious Diseases

Publisher

American Society for Microbiology

Subject

Infectious Diseases,Pharmacology (medical),Pharmacology

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