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

Tadeja Lukežič, Urška Lešnik, Ajda Podgoršek, Jaka Horvat, Tomaž Polak, Martin Šala, Branko Jenko, Peter Raspor, Paul R Herron, Iain S Hunter, Hrvoje Petković

Research output: Contribution to journalArticle

12 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2524-2532
Number of pages9
JournalMicrobiology
Volume159
Issue number12
Early online date16 Sep 2013
DOIs
Publication statusPublished - Dec 2013

Keywords

  • actinomycetales
  • anti-bacterial agents
  • biosynthetic pathways
  • DNA, bacterial
  • molecular sequence data
  • multigene family
  • open reading frames
  • sequence analysis, DNA
  • tetracyclines

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