Antifungal Chemical Compounds Identified Using a C. elegans Pathogenicity Assay

PLoS Pathogens

Eleftherios Mylonakis¹  Frederick M Ausubel²  Terence I Moy²  George Aperis³  Beth Burgwyn Fuchs³  Julia Breger³ 

[1] Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America;Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America;Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, United States of America

关键词: C;    ida albicans;    Caenorhabditis elegans;    Nematode infections;    Antifungals;    C;    ida;    Biofilms;    Library screening;    Gastrointestinal tract;   

DOI  :  10.1371/journal.ppat.0030018

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

There is an urgent need for the development of new antifungal agents. A facile in vivo model that evaluates libraries of chemical compounds could solve some of the main obstacles in current antifungal discovery. We show that Candida albicans, as well as other Candida species, are ingested by Caenorhabditis elegans and establish a persistent lethal infection in the C. elegans intestinal track. Importantly, key components of Candida pathogenesis in mammals, such as filament formation, are also involved in nematode killing. We devised a Candida-mediated C. elegans assay that allows high-throughput in vivo screening of chemical libraries for antifungal activities, while synchronously screening against toxic compounds. The assay is performed in liquid media using standard 96-well plate technology and allows the study of C. albicans in non-planktonic form. A screen of 1,266 compounds with known pharmaceutical activities identified 15 (∼1.2%) that prolonged survival of C. albicans-infected nematodes and inhibited in vivo filamentation of C. albicans. Two compounds identified in the screen, caffeic acid phenethyl ester, a major active component of honeybee propolis, and the fluoroquinolone agent enoxacin exhibited antifungal activity in a murine model of candidiasis. The whole-animal C. elegans assay may help to study the molecular basis of C. albicans pathogenesis and identify antifungal compounds that most likely would not be identified by in vitro screens that target fungal growth. Compounds identified in the screen that affect the virulence of Candida in vivo can potentially be used as “probe compounds” and may have antifungal activity against other fungi.

【 授权许可】

CC BY