amphotericin-b and octenidine

We compared the potency of four derivatives of the antimicrobial peptide halictine-2 against six Candida species. Observed activity was peptide and species specific. Halictines rapidly permeabilized cell membranes and caused the leakage of cytosolic components. Their killing potential was enhanced by the commercial antimicrobial agent octenidine dihydrochloride. The effect on C. glabrata cells did not depend on the activity of Cdr pumps, but was influenced by their lipid composition. The pre-treatment of cells with myriocin, an inhibitor of sphingolipid synthesis, enhanced the peptides' activity, whereas pre-treatment with terbinafine and fluconazole, inhibitors of sterol synthesis, significantly weakened their efficacy. The killing efficacy of peptides increased in combination with amphotericin B. Thus the mode of action of halictines is likely to depend on the plasma-membrane sterols, which might explain the observed differences among the tested Candida species.

Topics: Amphotericin B; Anti-Infective Agents; Antifungal Agents; Candida; Cell Membrane; Fatty Acids, Monounsaturated; Fluconazole; Imines; Lipids; Microbial Sensitivity Tests; Naphthalenes; Peptides; Pyridines; Sterols; Terbinafine

New antifungal agents are needed to treat life-threatening fungal infections, particularly with the development of resistance. Surface-active antifungals have the advantages of minimizing host toxicity and the emergence of drug resistance. We have developed a time-dependent drug exposure assay that allows us to rapidly investigate the mechanism of surface-active antifungal drug action. The assay uses a multidrug pump-deficient strain of Saccharomyces cerevisiae and the potentiometric dye 3,3'-dipropylthiacarbocyanine iodide [diS-C₃(3)] and can assess whether cells are depolarized, hyperpolarized, or permeabilized by drug exposure. In this work, we investigated the mechanisms of action of five surface-active compounds: SDS, nystatin, amphotericin B, octenidine dihydrochloride, and benzalkonium chloride. The diS-C₃(3) time-dependent drug exposure assay can be used to identify the mechanisms of action of a wide range of drugs. It is a fast and cost-effective method for screening drugs to determine their lowest effective concentrations.

Topics: Amphotericin B; Antifungal Agents; Benzalkonium Compounds; Cell Membrane Permeability; Imines; Kinetics; Microbial Sensitivity Tests; Nystatin; Pyridines; Saccharomyces cerevisiae; Sodium Dodecyl Sulfate; Spectrometry, Fluorescence; Surface-Active Agents

A series of bis(pyridinium)alkanes have been prepared and their antifungal activity, haemolytic activity and ability to inhibit fungal phospholipase B1 have been investigated, together with those of the commercially available antiseptics octenidine and dequalinium. Removal of the amino substituents from the pyridinium rings resulted in a significant decrease in antifungal activity. However, shortening or removing the alkyl chains attached to the amino groups had little effect on antifungal activity and significantly reduced haemolytic activity. Only octenidine was a strong inhibitor of fungal phospholipase B1.

Topics: Alkanes; Amphotericin B; Anti-Infective Agents, Local; Antifungal Agents; Candida albicans; Cryptococcus neoformans; Dequalinium; Enzyme Inhibitors; Fungi; Hemolytic Agents; Humans; Imines; In Vitro Techniques; Indicators and Reagents; Magnetic Resonance Spectroscopy; Microbial Sensitivity Tests; Mycoses; Phospholipases; Pyridines; Pyridinium Compounds; Structure-Activity Relationship