The increasing incidence of infections caused by drug-resistant pathogens requires new efforts for the discovery of novel antibiotics. By screening microbial extracts in an assay aimed at identifying compounds interfering with cell wall biosynthesis, based on differential activity against a Staphylococcus aureus strain and its isogenic l-form, the potent enduracyclinones (1, 2), containing the uncommon amino acid enduracididine linked to a six-ring aromatic skeleton, were discovered from different Nonomuraea strains. The structures of 1 and 2 were established through a combination of derivatizations, oxidative cleavages, and NMR analyses of natural and 13 C- 15 N-labeled compounds. Analysis of the biosynthetic cluster provides the combination of genes for the synthesis of enduracididine and type II polyketide synthases. Enduracyclinones are active against Gram-positive pathogens (especially Staphylococcus spp.), including multi-drug-resistant strains, with minimal inhibitory concentrations in the range of 0.0005 to 4 μg mL -1 and with limited toxicity toward eukaryotic cells. The combined results from assays and macromolecular syntheses suggest a possible dual mechanism of action in which both peptidoglycan and DNA syntheses are inhibited by these molecules.
Antibacterial Aromatic Polyketides Incorporating the Unusual Amino Acid Enduracididine / P. Monciardini, A. Bernasconi, M. Iorio, C. Brunati, M. Sosio, L. Campochiaro, P. Landini, S.I. Maffioli, S. Donadio. - In: JOURNAL OF NATURAL PRODUCTS. - ISSN 0163-3864. - 82:1(2019 Jan), pp. 35-44.
|Titolo:||Antibacterial Aromatic Polyketides Incorporating the Unusual Amino Acid Enduracididine|
|Parole Chiave:||Anti-Bacterial Agents; Data Mining; Multigene Family; Polyketides; Pyrrolidines|
|Settore Scientifico Disciplinare:||Settore BIO/19 - Microbiologia Generale|
|Data di pubblicazione:||gen-2019|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1021/acs.jnatprod.8b00354|
|Appare nelle tipologie:||01 - Articolo su periodico|