Synthesis, Antifungal Activity and Cytotoxicity of Novel Bis-Pyridinum Salts

Katrina A. Jolliffe,a Daniel Obando,a Fred Widmer,b Rosemary Handke,c Namfon Pantarat,b David H. Ellis,c Tania C. Sorrellb

Author address: 

a School of Chemistry, The University of Sydney, NSW, Australia; b Centre for Infectious Diseases and Microbiology, The University of Sydney at Westmead Hospital, NSW,Australia; c Womens and Childrens Hospital, Adelaide, SA, Australia([email protected]

Abstract: 

Background: Invasive fungal infections are a serious health issue and it is widely recognised that new antifungal drugs with novel modes of action are required. Fungal phospholipase B (PLB1) is a virulence factor in a number of pathogenic fungi.1,2 Using a series of bis-ammonium compounds, we have partly validated this multifunctional enzyme as a new antifungal drug target.3 We now report the antifungal activity spectrum, inhibition of PLB1, cytotoxicity and haemolytic activity of a recently discovered class of novel bis-(alkylpyridinium)alkane salts. Methods: The MICs of 33 compounds against ATCC reference strains of C. neoformans and C. albicans were determined. A subset of 10 of these compounds was tested against 13 yeasts and 15 moulds. MICs were determined as described3 using the CLSI methods for yeasts and filamentous fungi. All tests were performed in duplicate in two independent experiments. PLB1 inhibition, haemolytic activity and cytotoxicity (toward A549 and MDCK cells) were determined using published methods.3,4 Results: Four compounds with low cytotoxicity (IC50 > 200 !M; 0% haemolysis at 175 !M) had an MIC range of 1.4 150; 11 !M (0.85 150; 6.6 !g/ml, based on a FW of 600) against 11 yeasts, whereas 2 yeasts were 147;resistant148; with MICs of 87.5 !M. Scedosporium spp. and Exophiala spp. were the most sensitive moulds (MIC range of 0.7 150; 5.5 !M), whereas the range for Aspergillus spp. and F. solani was 11 150; 87.5 !M. Conclusions: Certain bis-(alkylpyridinium)alkane salts are potent against yeasts and emerging moulds. Further investigations in vitro and in animal models are in progress.
2007

abstract No: 

F1-940

Full conference title: 

47th Interscience Conference on Antimicrobial Agents and Chemotherapy
    • ICAAC 47th