Potent Fungicidal Activity Of Bis-amidine Antibiotics

Ref ID: 18744

Author:

T. J. Opperman, Ph.D – Senior Research Scientist, S. M. Kwasny, MS – Research Scientist, S. Nguyen, PhD – Senior Research Scientist, J. D. Williams, PhD – Senior Research Scientist, N. P. Peet, PhD – Director of Chemistry, T. L. Bowlin, PhD – Chief E

Author address:

Microbiotix, Inc., Worcester, MA.

Full conference title:

52nd Annual ICAAC

Date: 9 September 2014

Abstract:

Background: We have developed a series of bis-amidine (BA) containing compounds that are potent, broad spectrum antibacterial agents with a novel mechanism of action (MOA), which results in rapid bactericidal activity. BAs inhibit DNA and RNA synthesis by binding the minor groove of DNA, and inhibit cell wall synthesis through an unknown mechanism. To determine whether the spectrum of activity of BAs include fungal pathogens, we measured the antifungal (MIC) and fungicidal activities of several analogs against Candida albicans, C. krusei, and Cryptococcus neoformans. Methods: Antifungal MICs against three strains each of Candida albicans, C. krusei, and Crytococcus neoformans and time-dependent killing curves against C. albicans were determined according to CLSI guidelines. The effect of BAs on the incorporation of radiolabeled precursors into the major macromolecular synthetic pathways was measured using a published method. Enhanced fluorescence of BA compounds in the presence of DNA was visualized in intact C. albicans using fluorescence microscopy. Results: The BA analogs exhibited potent antifungal activity against C. albicans, C. krusei, and C. neoformans with MICs ranging between 0.125-2 µg/ml, 0.125-8 µg/ml, and 0.06-4 µg/ml, respectively. The most potent BAs were comparable to Amphotericin B (MIC 0.125 µg/ml). The three BAs tested in time kill experiments exhibited rapid fungicidal activity (>3 log10 decrease in cfu/ml in 4 h) at concentrations equivalent to 4x MIC. The BAs strongly inhibited DNA, RNA and cell wall biosynthesis in C. albicans. In situ fluorescence of the BAs, which exhibit enhanced fluorescence in the presence of DNA, was localized to the nucleus in intact cells of C. albicans. Conclusions: The BAs are potent antifungal agents with rapid fungicidal activity. It is likely that DNA-binding is the primary MOA for the antifungal as well as the antibacterial activity of these compounds.

Abstract Number: F-816

Conference Year: 2012

Link to conference website: NULL

New link: NULL

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