Solution NMR structure of five representative glycosylated polyene macrolide antibiotics with a sterol-dependent antifungal activity.
Glycosylated polyene macrolide antibiotics, as nystatins and amphotericins, are amphiphilic structures known to exert antifungal activity by disrupting the fungal cell membrane, leading to leakage of cellular materials, and cell death. This membrane disruption is strongly influenced by the presence and the exact nature of the membrane sterols. The solution structures of five representative glycosylated members, three tetraenes (pimaricin, nystatin A1 and rimocidin) and two heptaenes (candidin and vacidin A) have been calculated using geometric restraints derived from 1H-NMR data and random searches of their conformational space. Despite a different apparent structural order, the NMR solutions structure indicate that the hydroxyl groups all clustered on one side of the rod-shaped structures, and the glycosyl moieties are structurally conserved both in their conformation and their apparent order. The molecular structures afford an understanding of their selective interaction with the membrane sterols and the design of new polyene macrolides with improved activities.
Volpon
Laurent
L
Laboratoire de RMN Biomoléculaire associé au CNRS, Université Claude Bernard - Lyon 1 and Ecole Supérieure de Chimie Physique & Electronique de Lyon, Villeurbanne, France.
Lancelin
Jean-Marc
JM
D000900:Anti-Bacterial Agents / Q000737:chemistry*; D000935:Antifungal Agents / Q000737:chemistry*; D002174:Candicidin / Q000031:analogs & derivatives* / Q000737:chemistry; D006031:Glycosylation; D018942:Macrolides; D009682:Magnetic Resonance Spectroscopy; D010866:Natamycin / Q000737:chemistry; D009761:Nystatin / Q000737:chemistry; D011090:Polyenes / Q000737:chemistry*; D013261:Sterols / Q000378:metabolism
D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D018942:Macrolides; D011090:Polyenes; D013261:Sterols; D009761:Nystatin; D002174:Candicidin; C010428:candidin; C031985:vacidin A; C003273:rimocidin; D010866:Natamycin