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Original Research ARTICLE

Front. Microbiol. | doi: 10.3389/fmicb.2017.01145

The conserved actinobacterial two-component system MtrAB coordinates chloramphenicol production with sporulation in Streptomyces venezuelae NRRL B-65442

Nicolle F. Som1, Daniel Heine2, Neil A. Holmes1, John T. Munnoch1, Govind Chandra2, Ryan F. Seipke1, 3, Paul A. Hoskisson4, Barrie Wilkinson2 and Matthew I. Hutchings1*
  • 1School of Biological Sciences, University of East Anglia, United Kingdom
  • 2Molecular Microbiology, John Innes Centre, United Kingdom
  • 3University of Leeds, United Kingdom
  • 4University of Strathclyde, United Kingdom

Streptomyces bacteria make numerous secondary metabolites, including half of all known antibiotics. Production of antibiotics is usually coordinated with the onset of sporulation but the cross regulation of these processes is not fully understood. This is important because most Streptomyces antibiotics are produced at low levels or not at all under laboratory conditions and this makes large scale production of these compounds very challenging. Here we characterise the highly conserved actinobacterial two-component system MtrAB in the model organism Streptomyces venezuelae and provide evidence that it coordinates production of the antibiotic chloramphenicol with sporulation. MtrAB are known to coordinate DNA replication and cell division in Mycobacterium tuberculosis where TB-MtrA is essential for viability. We were unable to delete mtrA in S. venezuelae unless another copy was present in trans but deletion of mtrB resulted in a global shift in the metabolome, including constitutive, high-level production of chloramphenicol. We found that chloramphenicol is detectable in the wild type strain, but only at very low levels and only after it has sporulated. ChIP-seq showed that MtrA binds upstream of DNA replication and cell division genes and genes required for chloramphenicol production. dnaA, dnaN, oriC and wblE (whiB1) appear to be targets for MtrA in both M. tuberculosis and S. venezuelae. Intriguingly, over-expression of TB-MtrA and gain of function TB- and Sv-MtrA proteins in S. venezuelae also switched on high level production of chloramphenicol. Given the conservation of MtrAB, these constructs might be useful tools for manipulating antibiotic production in other filamentous actinomycetes.

Keywords: Chloramphenicol, Cell Division, mtrA, Streptomyces, antibiotics

Received: 05 May 2017; Accepted: 06 Jun 2017.

Edited by:

Yuji Morita, Aichi Gakuin University, Japan

Reviewed by:

Margarita Díaz, University of Salamanca, Spain
David L. Jakeman, Dalhousie University, Canada
Marie Elliot, McMaster University, Canada  

Copyright: © 2017 Som, Heine, Holmes, Munnoch, Chandra, Seipke, Hoskisson, Wilkinson and Hutchings. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Matthew I. Hutchings, University of East Anglia, School of Biological Sciences, Norwich Research Park, Norwich, NR47TJ, United Kingdom, m.hutchings@uea.ac.uk