Biosynthesis of pleuromutilin congeners using an Aspergillus oryzae expression platform

Fabrizio Alberti; Khairunisa Khairudin; Jonathan Davies; Suphattra Sangmalee; Chris L Willis; Gary D Foster; Andrew M. Bailey

doi:10.1039/d2sc06638f

Biosynthesis of pleuromutilin congeners using an Aspergillus oryzae expression platform

Fabrizio Alberti
, Khairunisa Khairudin
, Jonathan Davies
, Suphattra Sangmalee
, Chris L Willis
, Gary D Foster
, Andrew M. Bailey

Research output: Contribution to journal › Article (Academic Journal) › peer-review

12 Citations (Scopus)

Abstract

Pleuromutilin is an antibiotic diterpenoid made by Clitopilus passeckerianus and related fungi, and it is the
progenitor of a growing class of semi-synthetic antibiotics used in veterinary and human medicine. To
harness the biotechnological potential of this natural product class, a full understanding of its
biosynthetic pathway is essential. Previously, a linear pathway for pleuromutilin biosynthesis was
established. Here we report two shunt pathways involving Pl-sdr and Pl-atf that were identified through
the rational heterologous expression of combinations of pleuromutilin biosynthetic genes in Aspergillus
oryzae. Three novel pleuromutilin congeners were isolated, and their antimicrobial activity was
investigated, alongside that of an additional derivative produced through a semi-synthetic approach. It
was observed that the absence of various functional groups – 3 ketone, 11 hydroxyl group or 21 ketone
– from the pleuromutilin framework affected the antibacterial activity of pleuromutilin congeners. This
study expands our knowledge on the biosynthesis of pleuromutilin and provides avenues for the
development of novel pleuromutilin analogues by combining synthetic biology and synthetic chemistry.

Original language	English
Pages (from-to)	3826-3833
Number of pages	8
Journal	Chemical Science
Volume	14
Issue number	14
DOIs	https://doi.org/10.1039/d2sc06638f
Publication status	Published - 15 Mar 2023

Bibliographical note

Funding Information:
Dr Colin Lazarus is thanked for providing expression vectors for the transformation of A. oryzae; the NMR spectroscopy and MS facilities and teams of the University of Bristol are thanked for data collection and helpful discussion. KK was supported by a scholarship from Majlis Amanah Rakyat. JAD was supported by a scholarship from the EPSRC, Bristol Chemical Sciences Centre for Doctoral Training (EP/L015366/1). FA would like to acknowledge current funding from UKRI through a Future Leaders Fellowship (MR/V022334/1).

Publisher Copyright:
© 2023 The Royal Society of Chemistry.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Research Groups and Themes

BCS and TECS CDTs
Bristol BioDesign Institute
Organic & Biological

Keywords

synthetic biology

Access to Document

10.1039/d2sc06638fLicence: CC BY

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Cite this

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title = "Biosynthesis of pleuromutilin congeners using an Aspergillus oryzae expression platform",

abstract = "Pleuromutilin is an antibiotic diterpenoid made by Clitopilus passeckerianus and related fungi, and it is the progenitor of a growing class of semi-synthetic antibiotics used in veterinary and human medicine. To harness the biotechnological potential of this natural product class, a full understanding of its biosynthetic pathway is essential. Previously, a linear pathway for pleuromutilin biosynthesis was established. Here we report two shunt pathways involving Pl-sdr and Pl-atf that were identified through the rational heterologous expression of combinations of pleuromutilin biosynthetic genes in Aspergillus oryzae. Three novel pleuromutilin congeners were isolated, and their antimicrobial activity was investigated, alongside that of an additional derivative produced through a semi-synthetic approach. It was observed that the absence of various functional groups {\textendash} 3 ketone, 11 hydroxyl group or 21 ketone {\textendash} from the pleuromutilin framework affected the antibacterial activity of pleuromutilin congeners. This study expands our knowledge on the biosynthesis of pleuromutilin and provides avenues for the development of novel pleuromutilin analogues by combining synthetic biology and synthetic chemistry.",

keywords = "synthetic biology",

author = "Fabrizio Alberti and Khairunisa Khairudin and Jonathan Davies and Suphattra Sangmalee and Willis, \{Chris L\} and Foster, \{Gary D\} and Bailey, \{Andrew M.\}",

note = "Funding Information: Dr Colin Lazarus is thanked for providing expression vectors for the transformation of A. oryzae; the NMR spectroscopy and MS facilities and teams of the University of Bristol are thanked for data collection and helpful discussion. KK was supported by a scholarship from Majlis Amanah Rakyat. JAD was supported by a scholarship from the EPSRC, Bristol Chemical Sciences Centre for Doctoral Training (EP/L015366/1). FA would like to acknowledge current funding from UKRI through a Future Leaders Fellowship (MR/V022334/1). Publisher Copyright: {\textcopyright} 2023 The Royal Society of Chemistry.",

year = "2023",

month = mar,

day = "15",

doi = "10.1039/d2sc06638f",

language = "English",

volume = "14",

pages = "3826--3833",

journal = "Chemical Science",

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publisher = "Royal Society of Chemistry",

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AU - Alberti, Fabrizio

AU - Khairudin, Khairunisa

AU - Davies, Jonathan

AU - Sangmalee, Suphattra

AU - Willis, Chris L

AU - Foster, Gary D

AU - Bailey, Andrew M.

N1 - Funding Information: Dr Colin Lazarus is thanked for providing expression vectors for the transformation of A. oryzae; the NMR spectroscopy and MS facilities and teams of the University of Bristol are thanked for data collection and helpful discussion. KK was supported by a scholarship from Majlis Amanah Rakyat. JAD was supported by a scholarship from the EPSRC, Bristol Chemical Sciences Centre for Doctoral Training (EP/L015366/1). FA would like to acknowledge current funding from UKRI through a Future Leaders Fellowship (MR/V022334/1). Publisher Copyright: © 2023 The Royal Society of Chemistry.

PY - 2023/3/15

Y1 - 2023/3/15

N2 - Pleuromutilin is an antibiotic diterpenoid made by Clitopilus passeckerianus and related fungi, and it is the progenitor of a growing class of semi-synthetic antibiotics used in veterinary and human medicine. To harness the biotechnological potential of this natural product class, a full understanding of its biosynthetic pathway is essential. Previously, a linear pathway for pleuromutilin biosynthesis was established. Here we report two shunt pathways involving Pl-sdr and Pl-atf that were identified through the rational heterologous expression of combinations of pleuromutilin biosynthetic genes in Aspergillus oryzae. Three novel pleuromutilin congeners were isolated, and their antimicrobial activity was investigated, alongside that of an additional derivative produced through a semi-synthetic approach. It was observed that the absence of various functional groups – 3 ketone, 11 hydroxyl group or 21 ketone – from the pleuromutilin framework affected the antibacterial activity of pleuromutilin congeners. This study expands our knowledge on the biosynthesis of pleuromutilin and provides avenues for the development of novel pleuromutilin analogues by combining synthetic biology and synthetic chemistry.

AB - Pleuromutilin is an antibiotic diterpenoid made by Clitopilus passeckerianus and related fungi, and it is the progenitor of a growing class of semi-synthetic antibiotics used in veterinary and human medicine. To harness the biotechnological potential of this natural product class, a full understanding of its biosynthetic pathway is essential. Previously, a linear pathway for pleuromutilin biosynthesis was established. Here we report two shunt pathways involving Pl-sdr and Pl-atf that were identified through the rational heterologous expression of combinations of pleuromutilin biosynthetic genes in Aspergillus oryzae. Three novel pleuromutilin congeners were isolated, and their antimicrobial activity was investigated, alongside that of an additional derivative produced through a semi-synthetic approach. It was observed that the absence of various functional groups – 3 ketone, 11 hydroxyl group or 21 ketone – from the pleuromutilin framework affected the antibacterial activity of pleuromutilin congeners. This study expands our knowledge on the biosynthesis of pleuromutilin and provides avenues for the development of novel pleuromutilin analogues by combining synthetic biology and synthetic chemistry.

KW - synthetic biology

U2 - 10.1039/d2sc06638f

DO - 10.1039/d2sc06638f

M3 - Article (Academic Journal)

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SN - 2041-6520

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JO - Chemical Science

JF - Chemical Science

IS - 14

ER -

Biosynthesis of pleuromutilin congeners using an Aspergillus oryzae expression platform

Abstract

Bibliographical note

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Keywords

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