title: Biosynthesis of amphotericin derivatives lacking exocyclic carboxyl groups.
abstract: Amphotericin B is a medically important antifungal antibiotic that is also active against human immunodeficiency virus, Leishmania parasites, and prion diseases. The therapeutic use of amphotericin B is restricted by severe side effects that can be moderated by liposomal formulation or structural alteration. Chemical modification has shown that suppression of charge on the exocyclic carboxyl group of amphotericin B substantially reduces toxicity. We report targeted deletions of the amphN cytochrome P450 gene from the chromosome of the amphotericin-producing bacterium Streptomyces nodosus. The mutant strains produced amphotericin analogues in which methyl groups replace the exocyclic carboxyl groups. These compounds retained antifungal activity and had reduced hemolytic activity.
authors.affiliation: Department of Industrial Microbiology, Centre for Synthesis and Chemical Biology, Conway Institute for Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Maria
authors.initials: M
authors.lastname: Carmody
authors.forename: Barry
authors.initials: B
authors.lastname: Murphy
authors.forename: Barry
authors.initials: B
authors.lastname: Byrne
authors.forename: Patrick
authors.initials: P
authors.lastname: Power
authors.forename: Dilip
authors.initials: D
authors.lastname: Rai
authors.forename: Bernard
authors.initials: B
authors.lastname: Rawlings
authors.forename: Patrick
authors.initials: P
authors.lastname: Caffrey
mesh_terms: D000666:Amphotericin B / Q000031:analogs & derivatives* / Q000096:biosynthesis* / Q000737:chemistry; D000935:Antifungal Agents / Q000096:biosynthesis* / Q000737:chemistry; D001435:Bacteriophages / Q000378:metabolism; D002244:Carbon / Q000737:chemistry; D003001:Cloning, Molecular; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000235:genetics*; D004926:Escherichia coli / Q000378:metabolism; D017353:Gene Deletion; D008081:Liposomes / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008956:Models, Chemical; D005810:Multigene Family / Q000235:genetics; D009154:Mutation; D011090:Polyenes / Q000737:chemistry; D017434:Protein Structure, Tertiary; D011995:Recombination, Genetic; D021241:Spectrometry, Mass, Electrospray Ionization; D013302:Streptomyces / Q000378:metabolism
chemical_list: D000935:Antifungal Agents; D008081:Liposomes; D011090:Polyenes; D002244:Carbon; D000666:Amphotericin B; D003577:Cytochrome P-450 Enzyme System