%0 Journal Article %A Lukežič, Tadeja %A Lešnik, Urška %A Podgoršek, Ajda %A Horvat, Jaka %A Polak, Tomaž %A Šala, Martin %A Jenko, Branko %A Raspor, Peter %A Herron, Paul R. %A Hunter, Iain S. %A Petković, Hrvoje %T Identification of the chelocardin biosynthetic gene cluster from Amycolatopsis sulphurea: a platform for producing novel tetracycline antibiotics %D 2013 %J Microbiology, %V 159 %N Pt_12 %P 2524-2532 %@ 1465-2080 %R https://doi.org/10.1099/mic.0.070995-0 %I Microbiology Society, %X Tetracyclines (TCs) are medically important antibiotics from the polyketide family of natural products. Chelocardin (CHD), produced by Amycolatopsis sulphurea, is a broad-spectrum tetracyclic antibiotic with potent bacteriolytic activity against a number of Gram-positive and Gram-negative multi-resistant pathogens. CHD has an unknown mode of action that is different from TCs. It has some structural features that define it as ‘atypical’ and, notably, is active against tetracycline-resistant pathogens. Identification and characterization of the chelocardin biosynthetic gene cluster from A. sulphurea revealed 18 putative open reading frames including a type II polyketide synthase. Compared to typical TCs, the chd cluster contains a number of features that relate to its classification as ‘atypical’: an additional gene for a putative two-component cyclase/aromatase that may be responsible for the different aromatization pattern, a gene for a putative aminotransferase for C-4 with the opposite stereochemistry to TCs and a gene for a putative C-9 methylase that is a unique feature of this biosynthetic cluster within the TCs. Collectively, these enzymes deliver a molecule with different aromatization of ring C that results in an unusual planar structure of the TC backbone. This is a likely contributor to its different mode of action. In addition CHD biosynthesis is primed with acetate, unlike the TCs, which are primed with malonamate, and offers a biosynthetic engineering platform that represents a unique opportunity for efficient generation of novel tetracyclic backbones using combinatorial biosynthesis. %U https://www.microbiologyresearch.org/content/journal/micro/10.1099/mic.0.070995-0