MM-86553: a Novel Anti-Invasin antifungal Compound with Activity against Fluconazole-Resistant Candida albicans

M.E. MAYORGA, M. ASKENAZI, J. O'LEARY, A. FRETZEN, E.F. SUMMERS, G.T. MILNE

Author address: 

Microbia Inc., Cambridge, MA.

Abstract: 

Background: Anti-invasins are a new class of antifungal agents that inhibit the ability of C. albicans to initiate a pathogenic program including the morphological transition from yeast to hyphal growth. Due to their unique mode of action, we expect anti-invasin compounds to have a low likelihood of cross-resistance with known antifungal drugs. To test this hypothesis we measured the activity of a potent anti-invasin compound, MM-86553, against 130 C. albicans clinical isolates of which 37 were fluconazole (FLU) resistant (MIC ³ 64µg/ml). These isolates were obtained from the mouths of AIDS patients and from blood cultures. Methods: Strains were grown in YNB pH 4.5 overnight at 27°C and then transferred to RPMI medium for 24hrs with and without 20µM MM-86553 added. Effects on morphology where assessed by microscopic observation. Isolates that showed 5% hyphae were scored as ``resistant.'' Compound effects were further quantified for ``hyphal score'' using a morphometric algorithm that analyzes micrographs of compound and control treated strains. Strains sensitive to MM-86553 were characterized by a >10-fold decrease in hyphal scores when compound was added. Results: Of 130 clinical isolates examined, 121 formed hyphae in these conditions. 94% of these strains were sensitive to MM-86553. Fluconazole resistant clinical isolates were as sensitive to MM-86553 as fluconazole sensitive strains (31/33 [94%] FLUR vs. 83/88 [94%] FLUS). Conclusions: Nearly all C. albicans clinical isolates tested, including many fluconazole resistant strains, were sensitive to MM-86553. These results underscore the promise of this class of compounds for the treatment of resistant fungal infections.
2003

abstract No: 

F-1233

Full conference title: 

43rd Interscience Conference on Antimicrobial Agents
    • ICAAC 43rd