Identification of the chelocardin biosynthetic gene cluster from Amycolatopsis sulphurea : a platform for producing novel tetracycline antibiotics

Lukežič, Tadeja and Lešnik, Urška and Podgoršek, Ajda and Horvat, Jaka and Polak, Tomaž and Šala, Martin and Jenko, Branko and Raspor, Peter and Herron, Paul R and Hunter, Iain S and Petković, Hrvoje (2013) Identification of the chelocardin biosynthetic gene cluster from Amycolatopsis sulphurea : a platform for producing novel tetracycline antibiotics. Microbiology, 159 (12). pp. 2524-2532. ISSN 1350-0872

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Abstract

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.