Biosynthesis of amphotericin derivatives lacking exocyclic carboxyl groups.
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.
Carmody
Maria
M
Department of Industrial Microbiology, Centre for Synthesis and Chemical Biology, Conway Institute for Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland.
Murphy
Barry
B
Byrne
Barry
B
Power
Patrick
P
Rai
Dilip
D
Rawlings
Bernard
B
Caffrey
Patrick
P
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
D000935:Antifungal Agents; D008081:Liposomes; D011090:Polyenes; D002244:Carbon; D000666:Amphotericin B; D003577:Cytochrome P-450 Enzyme System