TY - JOUR

T1 - Identification and manipulation of the pleuromutilin gene cluster from Clitopilus passeckerianus for increased rapid antibiotic production

AU - Bailey, Andy M.

AU - Alberti, Fabrizio

AU - Kilaru, Sreedhar

AU - Collins, Catherine M.

AU - De Mattos-Shipley, Kate

AU - Hartley, Amanda J.

AU - Hayes, Patrick

AU - Griffin, Alison

AU - Lazarus, Colin M.

AU - Cox, Russell J.

AU - Willis, Christine L.

AU - O'Dwyer, Karen

AU - Spence, David W.

AU - Foster, Gary D.

N1 - Funding information: Much of this work was a follow on from BBSRC grant award to develop a Basidio Molecular Toolkit D19266. K.de M.-S. was supported through a BBSRC-G.S.K. CASE Award BB/E528379/1. P.H. and F.A. were both supported through University of Bristol Awards. S.K., C.M.C. and A.J.H. were all supported though funding from G.S.K. to the University of Bristol. Chemical analysis was performed on equipment provided by EPSRC EP/F066104/1 We also wish to thank Dr. Craig Butts for help with acquiring 500 MHz NMR data and Dr. Paul Gates from Bristol University Mass Spectrometry Service for help with obtaining HRMS data.

PY - 2016/5/4

Y1 - 2016/5/4

N2 - Semi-synthetic derivatives of the tricyclic diterpene antibiotic pleuromutilin from the basidiomycete Clitopilus passeckerianus are important in combatting bacterial infections in human and veterinary medicine. These compounds belong to the only new class of antibiotics for human applications, with novel mode of action and lack of cross-resistance, representing a class with great potential. Basidiomycete fungi, being dikaryotic, are not generally amenable to strain improvement. We report identification of the seven-gene pleuromutilin gene cluster and verify that using various targeted approaches aimed at increasing antibiotic production in C. passeckerianus, no improvement in yield was achieved. The seven-gene pleuromutilin cluster was reconstructed within Aspergillus oryzae giving production of pleuromutilin in an ascomycete, with a significant increase (2106%) in production. This is the first gene cluster from a basidiomycete to be successfully expressed in an ascomycete, and paves the way for the exploitation of a metabolically rich but traditionally overlooked group of fungi.

AB - Semi-synthetic derivatives of the tricyclic diterpene antibiotic pleuromutilin from the basidiomycete Clitopilus passeckerianus are important in combatting bacterial infections in human and veterinary medicine. These compounds belong to the only new class of antibiotics for human applications, with novel mode of action and lack of cross-resistance, representing a class with great potential. Basidiomycete fungi, being dikaryotic, are not generally amenable to strain improvement. We report identification of the seven-gene pleuromutilin gene cluster and verify that using various targeted approaches aimed at increasing antibiotic production in C. passeckerianus, no improvement in yield was achieved. The seven-gene pleuromutilin cluster was reconstructed within Aspergillus oryzae giving production of pleuromutilin in an ascomycete, with a significant increase (2106%) in production. This is the first gene cluster from a basidiomycete to be successfully expressed in an ascomycete, and paves the way for the exploitation of a metabolically rich but traditionally overlooked group of fungi.

UR - http://www.scopus.com/inward/record.url?scp=84965104303&partnerID=8YFLogxK

U2 - 10.1038/srep25202

DO - 10.1038/srep25202

M3 - Article

C2 - 27143514

AN - SCOPUS:84965104303

VL - 6

JO - Scientific reports

JF - Scientific reports

SN - 2045-2322

M1 - 25202

ER -