Antimicrobial and DNA Gyrase-Inhibitory Activities of Novel Clorobiocin Derivatives Produced by Mutasynthesis

Abstract

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.

New Aminocoumarin Antibiotics Derived from 4-Hydroxycinnamic Acid are Formed after Heterologous Expression of a Modified Clorobiocin Biosynthetic Gene Cluster

“…8Ј-Dechloro-3-chlorocoumarobiocin was less active than the two other compounds. This is consistent with earlier observations, which showed 80ϳ90% loss of antibacterial activity when the chlorine was removed from position 8Ј of the aminocoumarin antibiotics [16,18].…”

Synthesis, characterization, spectroscopic and crystallographic investigation of Cobalt(III) schiff base complex with two perpendicular diamine coumarin ligands

“…The Schiff base and the complex has been characterized by 1 H and 13 C NMR spectra. In 1 H NMR spectrum of the Schiff base, signal at 13.76 is ascribed to enolic-OH and the methyl protons from the acetyl fragment are identified at 2.07 ppm.…”

“…Coumarins and their derivatives [1,2] were found to exhibit a variety of biological and pharmacological activeties and have attracted considerable interest because of their potential beneficial effects on human health [3,4].…”

Characterization of the Aminocoumarin Ligase SimL from the Simocyclinone Pathway and Tandem Incubation with NovM,P,N from the Novobiocin Pathway

“…NovL, CloL, and CouL have been purified, and their ligase activity has been validated (13)(14)(15), providing the assurance that SimL is indeed the complementary simocyclinone ligase for simocyclinone biosynthesis. Previous efforts to introduce diversity in the aminocoumarins using the NovL, CloL, and CouL ligases have been limited by their specificity for benzoic acid or pyrrolecarboxylic acid sub-strates (16,17).…”