Antimicrobial activities of indolocarbazole and bis-indole protein kinase C inhibitors.

Abstract

The antimicrobial activities of twenty-twosubstances structurally related to staurosporine, aglycone in the indolocarbazole and bis-indole series were examined against Streptomyces chartreusis and Streptomyces griseus, Bacillus cereus, Escherichia coli, Candida albicans and Botrytis cinerea. Inhibition of sporulation was examined also on the two species of Streptomyces. Unlike literature reports for efficient protein kinase inhibitors, staurosporine and K-252a, no evident correlation could be found either between protein kinase inhibitory potencies and inhibition of sporulation of the Streptomyces species, or protein kinase inhibitory potencies and growth of all microorganisms tested.A weak activity against C. albicans was observed for the chloro-indolocarbazole compounds as already reported for structurally related substances from the cyanobacterium Tolypothrix tjipanasensis.Streptomycetes are Gram-positive bacteria which form a spore-producing aerial mycelium. It was found recently that the microbial indolocarbazole metabolites, staurosporine1) and K-252a2) (Fig. 1), inhibit aerial mycelium formation and antibiotic production by Streptomyces griseus3\ These compounds are knownalso as inhibitors of eukaryotic protein kinase C.To determine if there was a general link between activity on protein kinase C and inhibition of spore formation, the in vitro growth inhibitory effect of twenty-two compounds in the indolocarbazole andbis-indole series were tested against S. griseus and Streptomyces chartreusis. The activities of these twenty-two compoundstowards protein kinase C and protein kinase A have been determined previously; some of them were active, others not4~7). Production of the secondary metabolite calcimycin (A 23187) by S. chartreusis was examined when the culture was incubated with an efficient protein kinase C inhibitor and with a compound inactive towards this enzyme. The antimicrobial activities against Bacillus cereus, Escherichia coli, Candida albicans and Botrytis cinerea were determined also.

Combinatorial biosynthesis of antitumor indolocarbazole compounds

“…Studies have shown that some indolocarbazole compounds, such as rebeccamycin, inhibited the growth of streptomycete strains, whereas other indolocarbazole compounds, such as staurosporine, allowed growth but affected cell differentiation in the tested strains (36,37). Therefore, a possibility existed at the beginning of this study that some of the generated derivatives could affect the growth of the host, S. albus.…”

A Genomic Screening Approach to the Structure‐Guided Identification of Drug Candidates from Natural Sources

“…Halogenation is an important feature for the biological activity of a large number of different natural products. [39][40][41] The interest in and knowledge of halogenating enzymes is increasing rapidly. There are two subtypes of halogenases that are known to be involved in the biosynthesis of secondary metabolites: the FADH 2 -dependent halogenases that act upon aromatic or heteroaromatic rings, which is the subtype that was used in this study, and the recently discovered non-heme Fe II halogenases, which act on aliphatic groups.…”

Structural analysis of a non-ribosomal halogenated cyclic peptide and its putative operon from Microcystis: implications for evolution of cyanopeptolins

“…In many cases, the number, type and position of halogen groups in organic compounds are important for biological activity (see Nogami et al, 1990;Otsuka et al, 2004;Sancelme et al, 1994). Concerning cyanopeptolins, both chlorinated and non-chlorinated peptides have been described, e.g.…”