SYNERGISM BETWEEN THE ANTIFUNGAL AGENTS AMPHOTERICIN-B AND ALKYL GLYCEROL ETHERS

The alkyl glycerol ether rac-1-O-dodecylglycerol inhibited the growth of members of two genera of yeasts, Candida and Cryptococcus, and was strongly synergistic with amphotericin B. At one-half its MIC, dodecyl glycerol decreased the MIC of amphotericin B by as much as 80-fold. Th is high degree of synergism between dodecylglycerol and amphotericin B was demonstrated against a number of species of yeasts including Cand ida albicans, Candida tropicalis, Candida parapsilosis, Cryptococcus n eoformans, Cryptococcus albidus, and Cryptococcus laurentii. All fract ional inhibitory concentrations (for all strains and species) were cal culated to be less than 1, and most were less than 0.6, again demonstr ating strong synergism. Other alkyl glycerol ethers with alkyl chain l engths ranging from 8 to 18 carbon atoms were also found to be synergi stic with amphotericin B against C. neoformans and C. albicans. Electr on microscopy experiments showed that C. neoformans grown in the prese nce of dodecylglycerol had severely abnormal, deformed capsules. Altho ugh the mechanism of action of dodecylglycerol is not known, dodecylgl ycerol was not simply acting as a detergent. The natural detergent sod ium deoxycholate could not substitute for dodecylglycerol. At comparab le and higher concentrations, sodium deoxycholate had no fungicidal ef fect on its own, nor did it potentiate the activity of amphotericin B. Dodecylglycerol did not interact synergistically with the water-solub le antifungal agent fluconazole. The lipid-soluble hydrophobic propert ies of amphotericin B appear to be important for this synergistic effe ct, in that alkyl glycerol ethers could promote synergism with amphote ricin B by potentially increasing the interaction between membrane-bou nd ergosterol and amphotericin B.