TLN-05220, TLN-05223, new Echinosporamicin-type antibiotics, and proposed revision of the structure of bravomicins

Abstract

The deposited strain of the hazimicin producer, Micromonospora echinospora ssp. challisensis NRRL 12255 has considerable biosynthetic capabilities as revealed by genome scanning. Among these is a locus containing both type I and type II PKS genes. The presumed products of this locus, TLN-05220 (1) and TLN-05223 (2), bear a core backbone composed of six fused rings starting with a 2-pyridone moiety. The structures were confirmed by conventional spectral analyses including MS, and 1D and 2D NMR experiments. Comparison of both the 1 H and 13 C NMR data of the newly isolated compound with those of echinosporamicin and bravomicin A led us to propose a revision of the structure of the latter to include a 2-pyridone instead of the pyran originally postulated. Both compounds (1 and 2) possessed strong antibacterial activity against a series of grampositive pathogens including several strains of methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococci (VRE), and cytotoxic activities against several human tumor cell lines. The TLN compounds are the first of this group with reported anticancer activity.

Functional characterization of O -methyltransferases used to catalyse site-specific methylation in the post-tailoring steps of pradimicin biosynthesis

“…PdmF shows high sequence similarities to polyketomycin-8-O-methyltransferase (PokMT3, 50% identity), fredericamycin-11-O-methyltransferase (FdmN, 50% identity), tetracenomycin-3-O-methyltransferase (TcmN, 47% identity), and elloramycin-3-O-methyltransferase (47% identity; Summers et al 1992;Wendt-Pienkowski et al 2005;Ramos et al 2008;Daum et al 2009). The PdmT homologues are also found in the biosynthetic gene clusters of the aromatic polyketides TLN-05220 (Orf12, 55% identity), lactonamycin (Lct35, 51% identity), tetracenomycin C (TcmO, 50% identity) and lysolipin (LlpMVI, 49% identity; Summers et al 1992;Zhang et al 2008;Banskota et al 2009;Lopez et al 2010).…”

“…; Banskota et al . ; Zhan ). In bacteria, aromatic polyketides are synthesized by type II polyketide synthases (PKSs) in a way similar to bacterial fatty acid biosynthesis (Zhan ).…”

“…Aromatic polyketides constitute a large group of structurally and biologically diverse secondary metabolites. Their usefulness as pharmaceuticals and agrochemicals has promoted research into the discovery of novel polyketide metabolites with biological activities (Wendt-Pienkowski et al 2005;Zhang et al 2008;Banskota et al 2009;Zhan 2009). In bacteria, aromatic polyketides are synthesized by type II polyketide synthases (PKSs) in a way similar to bacterial fatty acid biosynthesis (Zhan 2009).…”

Clostridium difficile Drug Pipeline: Challenges in Discovery and Development of New Agents

“… Structures of ziracin 128 , 118 hydramycin 129 , 120 clerocidin 130 , 121 echinosporamicin-type antibiotics 131 and 132 , 123 merochlorin A 133 , 124 and olympicin A 134 , 126 and analogs 135 – 138 126 with activity against C. difficile . …”

Application of response surface methodology to optimize the production of antimicrobial metabolites by Micromonospora Y15

“…were discovered to produce novel antibacterial active substances (tetrocarcin, bafilolide metabolite, echinosporamicin, saquayamycin, etc.) [14][15][16][17].…”