Antimicrobial and DNA gyrase-inhibitory activities of novel clorobiocin derivatives produced by mutasynthesis.
Twenty-eight novel clorobiocin derivatives obtained from mutasynthesis experiments were investigated for their inhibitory activity towards Escherichia coli DNA gyrase and for their antibacterial activities towards clinically relevant gram-positive and gram-negative bacteria in comparison to novobiocin and clorobiocin. Clorobiocin was the most active compound both against E. coli DNA gyrase in vitro and against bacterial growth. All tested modifications of the 3-dimethylallyl-4-hydroxybenzoyl moiety reduced biological activity. The highest activities were shown by compounds containing a hydrophobic alkyl substituent at position 3 of the 4-hydroxybenzoyl moiety. Polar groups in this side chain, especially amide functions, strongly reduced antibacterial activity. Replacement of the alkyl side chain with a halogen atom or a methoxy group at the same position markedly reduced activity. Transfer of the pyrrole carboxylic acid moiety from O-3" to O-2" of L-noviose moderately reduced activity, whereas the complete absence of the pyrrole carboxylic acid moiety led to a loss of activity. Desclorobiocin derivatives lacking the chlorine atom at C-8 of the 3-amino-4,7-dihydroxycoumarin moiety also showed low activity. Lack of a methyl group at O-4" of L-noviose resulted in an inactive compound. From these findings it appears that clorobiocin represents a "highly evolved" structure optimized for bacterial transport and DNA gyrase inhibition.
Galm
Ute
U
Pharmazeutische Biologie, Pharmazeutisches Institut, D-72076 Tuebingen, Germany.
Heller
Stefanie
S
Shapiro
Stuart
S
Page
Malcolm
M
Li
Shu-Ming
SM
Heide
Lutz
L
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis / Q000494:pharmacology*; D001412:Bacillus subtilis / Q000187:drug effects; D001419:Bacteria / Q000187:drug effects*; D004278:DNA, Superhelical / Q000096:biosynthesis / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D009154:Mutation / Q000502:physiology*; D009675:Novobiocin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D013302:Streptomyces / Q000235:genetics* / Q000378:metabolism*; D059005:Topoisomerase II Inhibitors
D000900:Anti-Bacterial Agents; D000903:Antibiotics, Antineoplastic; D004278:DNA, Superhelical; D004791:Enzyme Inhibitors; D059005:Topoisomerase II Inhibitors; D009675:Novobiocin; C006260:clorobiocin