Novel avilamycin derivatives with improved polarity generated by targeted gene disruption.
The oligosaccharide antibiotics avilamycin A and C are produced by Streptomyces viridochromogenes Tu57. Both consist of a heptasaccharide chain, which is attached to a polyketide-derived dichloroisoeverninic acid moiety. They show excellent antibiotic activity against Gram-positive bacteria. Both molecules are modified by O-methylation at different positions, which contributes to poor water solubility and difficulties in galenical drug development. In order to generate novel avilamycin derivatives with improved polarity and improved pharmacokinetic properties, we generated a series of mutants with one, two, or three mutated methyltransferase genes. Based on the structure of the novel avilamycin derivatives, the exact function of three methyltransferases, AviG2, AviG5, and AviG6, involved in avilamycin biosynthesis could be assigned.
Pharmazeutische Biologie und Biotechnologie, Institut für Pharmazeutische Wissenschaften, Albert-Ludwigs-Universität Freiburg, Stefan-Meier-Strasse 19, 79104 Freiburg, Germany.
Gabriele
G
Weitnauer
Gerd
G
Hauser
Carsten
C
Hofmann
Ulrike
U
Linder
Raija
R
Boll
Klaus
K
Pelz
Steffen J
SJ
Glaser
Andreas
A
Bechthold
D018390:Gene Targeting / Q000379:methods*; D006094:Gram-Positive Bacteria / Q000187:drug effects; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D005810:Multigene Family; D019906:Nuclear Magnetic Resonance, Biomolecular; D009844:Oligosaccharides / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D013302:Streptomyces / Q000201:enzymology / Q000235:genetics
D009844:Oligosaccharides; C006653:avilamycin; D008780:Methyltransferases; C436976:avilamycin A