Genomic analyses lead to novel secondary metabolites. Part 3. ECO-0501, a novel antibacterial of a new class.
Genomic analyses of Amycolatopsis orientalis ATCC 43491 strain, deposited as a vancomycin producer, revealed the presence of genetic loci for the production of at least 10 secondary metabolites other than vancomycin. One of these gene clusters, which contained a type I polyketide synthase, was predicted to direct the synthesis of novel class of compound, a glycosidic polyketide ECO-0501 (1). Screening of culture extracts for a compound with the predicted physicochemical properties of the product from this locus, led to the isolation of the 13-O-glucuronide of 13-hydroxy-2,12,14,16,22-pentamethyl-28-(N-methyl-guanidino)-octacosa-2,4,6,8,10,14,20,24-octaenoic acid (2-hydroxy-5-oxo-cyclopent-1-enyl)-amide (ECO-0501, 1). The structure, confirmed by spectral analyses including MS, and ID and 2D NMR experiments, were in accord with that predicted by genomic analyses. ECO-0501 possessed strong antibacterial activity against a series of Gram-positive pathogens including several strains of methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE). ECO-0501 was chemically modified by esterification (1a-1c), N-acetylation (1d) and hydrogenation (1e) in order to explore structure activity relationships (SAR).
Banskota
Arjun H
AH
Ecopia BioSciences Inc., 7290 Frederick-Banting, Montreal, Quebec, H4S 2A1, Canada.
Mcalpine
James B
JB
Sørensen
Dan
D
Ibrahim
Ashraf
A
Aouidate
Mustapha
M
Piraee
Mahmood
M
Alarco
Anne-Marie
AM
Farnet
Chris M
CM
Zazopoulos
Emmanuel
E
D000192:Actinomycetales / Q000235:genetics* / Q000378:metabolism*; D000900:Anti-Bacterial Agents / Q000096:biosynthesis* / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D004269:DNA, Bacterial / Q000737:chemistry / Q000235:genetics; D016983:Enterococcus / Q000187:drug effects; D005231:Fatty Acids, Unsaturated / Q000096:biosynthesis* / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D005798:Genes, Bacterial; D023281:Genomics; D006146:Guanidines / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D016106:Methicillin Resistance; D008969:Molecular Sequence Data; D005810:Multigene Family; D010802:Phylogeny; D017386:Sequence Homology, Amino Acid; D013211:Staphylococcus aureus / Q000187:drug effects; D013329:Structure-Activity Relationship; D020713:Vancomycin Resistance
C515838:13-hydroxy-2,12,14,16,22-pentamethyl-28-(N-methyl-guanidino)-octacosa-2,4,6,8,10,14,20,24-octaenoic acid (2-hydroxy-5-oxo-cyclopent-1-enyl)-amide; D000900:Anti-Bacterial Agents; D004269:DNA, Bacterial; D005231:Fatty Acids, Unsaturated; D006146:Guanidines