Determining the Mode of Action of Ibomycin: A Novel Antifungal Compound

Abstract

Unlike their bacterial counterparts, diseases caused by fungal pathogens are harder to treat due to a lack of discrete targets. Current antifungals are very broad spectrum and fall into three major classes: polyenes which target the cell membrane, azoles which target sterol biosynthesis and the echinocandins which target the cell wall. Recently a novel macrolide antibiotic produced by WAC 2288 was discovered in a co-culturing screen between various actinomycetes and pathogenic fungi. The active compound, a large type I polyketide compound called ibomycin, was specifically able to inhibit the growth of Cryptococcus neoformans but not Candida albicans. A combination of traditional and genetic approaches were used to identify the mode of action of ibomycin. Despite having characteristics associated with membrane perturbing agents such as fungicidal activity, causing hemolysis and even membrane localization in vivo, it does not seem that ibomycin disrupts the membrane in a sterol-dependent manner. We found evidence to suggest that ibomycin is not involved in disruption of cell wall biosynthesis based on localization in vivo and absence of viability rescue in presence of sorbitol. The results of haploinsufficiency and homozygous profiling of yeast deletion strains suggest that is no single protein target for ibomycin, but rather that membrane perturbation of ibomycin leads to downstream effects that impair vesicular trafficking and protein transport. Based on preliminary evidence, it is predicted that C. albicans is able to bind ibomycin but evades the induced toxic effects by barring access to its cell membrane.