Identification of antifungal compounds active against Candida albicans using an improved high-throughput Caenorhabditis elegans assay.
Candida albicans, the most common human pathogenic fungus, can establish a persistent lethal infection in the intestine of the microscopic nematode Caenorhabditis elegans. The C. elegans-C. albicans infection model was previously adapted to screen for antifungal compounds. Modifications to this screen have been made to facilitate a high-throughput assay including co-inoculation of nematodes with C. albicans and instrumentation allowing precise dispensing of worms into assay wells, eliminating two labor-intensive steps. This high-throughput method was utilized to screen a library of 3,228 compounds represented by 1,948 bioactive compounds and 1,280 small molecules derived via diversity-oriented synthesis. Nineteen compounds were identified that conferred an increase in C. elegans survival, including most known antifungal compounds within the chemical library. In addition to seven clinically used antifungal compounds, twelve compounds were identified which are not primarily used as antifungal agents, including three immunosuppressive drugs. This assay also allowed the assessment of the relative minimal inhibitory concentration, the effective concentration in vivo, and the toxicity of the compound in a single assay.
Okoli
Ikechukwu
I
Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
Coleman
Jeffrey J
JJ
Tampakakis
Emmanouil
E
Tempakakis
Emmanouil
E
An
W Frank
WF
Holson
Edward
E
Wagner
Florence
F
Conery
Annie L
AL
Larkins-Ford
Jonah
J
Wu
Gang
G
Stern
Andy
A
Ausubel
Frederick M
FM
Mylonakis
Eleftherios
E
D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D017173:Caenorhabditis elegans; D002176:Candida albicans / Q000187:drug effects*; D002626:Chemistry, Pharmaceutical / Q000379:methods; D020650:Combinatorial Chemistry Techniques; D015195:Drug Design; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008826:Microbial Sensitivity Tests; D009154:Mutation
D000935:Antifungal Agents; D007166:Immunosuppressive Agents