Polyene antibiotic that inhibits membrane transport proteins.
The limited therapeutic arsenal and the increase in reports of fungal resistance to multiple antifungal agents have made fungal infections a major therapeutic challenge. The polyene antibiotics are the only group of antifungal antibiotics that directly target the plasma membrane via a specific interaction with the main fungal sterol, ergosterol, often resulting in membrane permeabilization. In contrast to other polyene antibiotics that form pores in the membrane, the mode of action of natamycin has remained obscure but is not related to membrane permeabilization. Here, we demonstrate that natamycin inhibits growth of yeasts and fungi via the immediate inhibition of amino acid and glucose transport across the plasma membrane. This is attributable to ergosterol-specific and reversible inhibition of membrane transport proteins. It is proposed that ergosterol-dependent inhibition of membrane proteins is a general mode of action of all the polyene antibiotics, of which some have been shown additionally to permeabilize the plasma membrane. Our results imply that sterol-protein interactions are fundamentally important for protein function even for those proteins that are not known to reside in sterol-rich domains.
Department of Biochemistry of Membranes, Institute of Biomembranes,  Utrecht University, 3584 CH Utrecht,  The Netherlands.
Yvonne Maria
YM
te Welscher
Martin Richard
MR
van Leeuwen
Ben
B
de Kruijff
Jan
J
Dijksterhuis
Eefjan
E
Breukink
D000596:Amino Acids / Q000737:chemistry; D000900:Anti-Bacterial Agents / Q000737:chemistry*; D000890:Anti-Infective Agents / Q000494:pharmacology; D001234:Aspergillus niger / Q000378:metabolism; D001692:Biological Transport; D002462:Cell Membrane / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004875:Ergosterol / Q000737:chemistry; D015966:Gene Expression Regulation, Fungal; D005947:Glucose / Q000378:metabolism; D008954:Models, Biological; D010866:Natamycin / Q000494:pharmacology; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D016366:Open Reading Frames; D010539:Permeability; D011090:Polyenes / Q000737:chemistry*; D012313:RNA / Q000378:metabolism; D012331:RNA, Fungal / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000378:metabolism
D000596:Amino Acids; D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents; D018076:DNA, Complementary; D011090:Polyenes; D012331:RNA, Fungal; D012313:RNA; D010866:Natamycin; D005947:Glucose; D004875:Ergosterol