An unusual Burkholderia gladioli double chain-initiating nonribosomal peptide synthetase assembles 'fungal' icosalide antibiotics

Matthew Jenner, Xinyun Jian, Yousef Dashti, Joleen Masschelein, Christian Hobson, Douglas M. Roberts, Cerith Jones, Simon Harris, Julian Parkhill, Huzefa A. Raja, Nicholas H. Oberlies, Cedric J. Pearce, Eshwar Mahenthiralingam, Gregory L. Challis

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Burkholderia is a multi-talented genus of Gram-negative bacteria, which in recent years has become increasingly recognised as a promising source of bioactive natural products. Metabolite profiling of Burkholderia gladioli BCC0238 showed that it produces the asymmetric lipopeptidiolide antibiotic icosalide A1, originally isolated from a fungus. Comparative bioinformatics analysis of several genome-sequenced B. gladioli isolates identified a gene encoding a nonribosomal peptide synthase (NRPS) with an unusual architecture that was predicted to be responsible for icosalide biosynthesis. Inactivation of this gene in B. gladioli BCC0238 abolished icosalide production. PCR analysis and sequencing of total DNA from the original fungal icosalide A1 producer revealed it has a B. gladioli strain associated with it that harbours an NRPS with an identical architecture to that responsible for icosalide A1 assembly in B. gladioli BCC0238. Sequence analysis of the icosalide NRPS indicated that it contains two chain-initiating condensation (CI) domains. One of these is appended to the N-terminus of module 1-a common architecture for NRPSs involved in lipopeptide assembly. The other is embedded in module 3, immediately downstream of a putative chain-elongating condensation domain. Analysis of the reactions catalysed by a tridomain construct from module 3 of the NRPS using intact protein mass spectrometry showed that the embedded CI domain initiates assembly of a second lipopeptide chain, providing key insights into the mechanism for asymmetric diolide assembly.

Original languageEnglish
Pages (from-to)5489-5494
Number of pages6
JournalChemical Science
Volume10
Issue number21
DOIs
Publication statusPublished - 25 Apr 2019

Cite this

Jenner, Matthew ; Jian, Xinyun ; Dashti, Yousef ; Masschelein, Joleen ; Hobson, Christian ; Roberts, Douglas M. ; Jones, Cerith ; Harris, Simon ; Parkhill, Julian ; Raja, Huzefa A. ; Oberlies, Nicholas H. ; Pearce, Cedric J. ; Mahenthiralingam, Eshwar ; Challis, Gregory L. / An unusual Burkholderia gladioli double chain-initiating nonribosomal peptide synthetase assembles 'fungal' icosalide antibiotics. In: Chemical Science. 2019 ; Vol. 10, No. 21. pp. 5489-5494.
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title = "An unusual Burkholderia gladioli double chain-initiating nonribosomal peptide synthetase assembles 'fungal' icosalide antibiotics",
abstract = "Burkholderia is a multi-talented genus of Gram-negative bacteria, which in recent years has become increasingly recognised as a promising source of bioactive natural products. Metabolite profiling of Burkholderia gladioli BCC0238 showed that it produces the asymmetric lipopeptidiolide antibiotic icosalide A1, originally isolated from a fungus. Comparative bioinformatics analysis of several genome-sequenced B. gladioli isolates identified a gene encoding a nonribosomal peptide synthase (NRPS) with an unusual architecture that was predicted to be responsible for icosalide biosynthesis. Inactivation of this gene in B. gladioli BCC0238 abolished icosalide production. PCR analysis and sequencing of total DNA from the original fungal icosalide A1 producer revealed it has a B. gladioli strain associated with it that harbours an NRPS with an identical architecture to that responsible for icosalide A1 assembly in B. gladioli BCC0238. Sequence analysis of the icosalide NRPS indicated that it contains two chain-initiating condensation (CI) domains. One of these is appended to the N-terminus of module 1-a common architecture for NRPSs involved in lipopeptide assembly. The other is embedded in module 3, immediately downstream of a putative chain-elongating condensation domain. Analysis of the reactions catalysed by a tridomain construct from module 3 of the NRPS using intact protein mass spectrometry showed that the embedded CI domain initiates assembly of a second lipopeptide chain, providing key insights into the mechanism for asymmetric diolide assembly.",
author = "Matthew Jenner and Xinyun Jian and Yousef Dashti and Joleen Masschelein and Christian Hobson and Roberts, {Douglas M.} and Cerith Jones and Simon Harris and Julian Parkhill and Raja, {Huzefa A.} and Oberlies, {Nicholas H.} and Pearce, {Cedric J.} and Eshwar Mahenthiralingam and Challis, {Gregory L.}",
year = "2019",
month = "4",
day = "25",
doi = "10.1039/c8sc04897e",
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Jenner, M, Jian, X, Dashti, Y, Masschelein, J, Hobson, C, Roberts, DM, Jones, C, Harris, S, Parkhill, J, Raja, HA, Oberlies, NH, Pearce, CJ, Mahenthiralingam, E & Challis, GL 2019, 'An unusual Burkholderia gladioli double chain-initiating nonribosomal peptide synthetase assembles 'fungal' icosalide antibiotics' Chemical Science, vol. 10, no. 21, pp. 5489-5494. https://doi.org/10.1039/c8sc04897e

An unusual Burkholderia gladioli double chain-initiating nonribosomal peptide synthetase assembles 'fungal' icosalide antibiotics. / Jenner, Matthew; Jian, Xinyun; Dashti, Yousef; Masschelein, Joleen; Hobson, Christian; Roberts, Douglas M.; Jones, Cerith; Harris, Simon; Parkhill, Julian; Raja, Huzefa A.; Oberlies, Nicholas H.; Pearce, Cedric J.; Mahenthiralingam, Eshwar; Challis, Gregory L.

In: Chemical Science, Vol. 10, No. 21, 25.04.2019, p. 5489-5494.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Jenner, Matthew

AU - Jian, Xinyun

AU - Dashti, Yousef

AU - Masschelein, Joleen

AU - Hobson, Christian

AU - Roberts, Douglas M.

AU - Jones, Cerith

AU - Harris, Simon

AU - Parkhill, Julian

AU - Raja, Huzefa A.

AU - Oberlies, Nicholas H.

AU - Pearce, Cedric J.

AU - Mahenthiralingam, Eshwar

AU - Challis, Gregory L.

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