Identification of inhibitors of drug-resistant Candida albicans strains from a library of bicyclic peptidomimetic compounds.
The screening of a library of small molecule peptidomimetics toward secreted aspartic proteinase-2 (SAP2) of Candida albicans allowed us to identify two compounds that showed in vitro inhibitory potency comparable to pepstatin A. In an experimental model of vaginal candidiasis, the two candidate compounds were as active as a therapeutic dose of fluconazole. Importantly, this activity was fully preserved when the challenger was a fluconazole-resistant strain of the fungus. Altogether, our data demonstrate SAP2 as a valid C. albicans target for the development of new drugs against this important human pathogen.
Trabocchi
Andrea
A
Department of Chemistry Ugo Schiff, University of Florence, Polo Scientifico e Tecnologico, Via della Lastruccia 13, 50019 Sesto Fiorentino, Florence, Italy.
Mannino
Claudia
C
Machetti
Fabrizio
F
De Bernardis
Flavia
F
Arancia
Silvia
S
Cauda
Roberto
R
Cassone
Antonio
A
Guarna
Antonio
A
D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002176:Candida albicans / Q000187:drug effects* / Q000201:enzymology / Q000472:pathogenicity; D002177:Candidiasis / Q000382:microbiology / Q000517:prevention & control; D004305:Dose-Response Relationship, Drug; D025141:Drug Resistance, Fungal / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D015725:Fluconazole / Q000494:pharmacology; D005656:Fungal Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008956:Models, Chemical; D015394:Molecular Structure; D010436:Pepstatins / Q000737:chemistry; D019151:Peptide Library; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D014774:Virulence
D000935:Antifungal Agents; D004791:Enzyme Inhibitors; D005656:Fungal Proteins; D010436:Pepstatins; D019151:Peptide Library; D010456:Peptides, Cyclic; D015725:Fluconazole; D016282:Aspartic Acid Endopeptidases; C090753:SAP2 protein, Candida; C031375:pepstatin