A Natural Plasmid Uniquely Encodes Two Biosynthetic Pathways Creating a Potent Anti-MRSA Antibiotic.

Research output: Contribution to journalArticle

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A Natural Plasmid Uniquely Encodes Two Biosynthetic Pathways Creating a Potent Anti-MRSA Antibiotic. / Fukuda, D; Haines, Anthony; Song, Z; Murphy, AC; Hothersall, Joanne; Stephens, Elton; Gurney, Rachel; Cox, RJ; Crosby, J; Willis, CL; Simpson, TJ; Thomas, Christopher.

In: PLoS ONE, Vol. 6, No. 3, 01.01.2011, p. e18031.

Research output: Contribution to journalArticle

Harvard

Fukuda, D, Haines, A, Song, Z, Murphy, AC, Hothersall, J, Stephens, E, Gurney, R, Cox, RJ, Crosby, J, Willis, CL, Simpson, TJ & Thomas, C 2011, 'A Natural Plasmid Uniquely Encodes Two Biosynthetic Pathways Creating a Potent Anti-MRSA Antibiotic.', PLoS ONE, vol. 6, no. 3, pp. e18031. https://doi.org/10.1371/journal.pone.0018031

APA

Fukuda, D., Haines, A., Song, Z., Murphy, AC., Hothersall, J., Stephens, E., Gurney, R., Cox, RJ., Crosby, J., Willis, CL., Simpson, TJ., & Thomas, C. (2011). A Natural Plasmid Uniquely Encodes Two Biosynthetic Pathways Creating a Potent Anti-MRSA Antibiotic. PLoS ONE, 6(3), e18031. https://doi.org/10.1371/journal.pone.0018031

Vancouver

Author

Fukuda, D ; Haines, Anthony ; Song, Z ; Murphy, AC ; Hothersall, Joanne ; Stephens, Elton ; Gurney, Rachel ; Cox, RJ ; Crosby, J ; Willis, CL ; Simpson, TJ ; Thomas, Christopher. / A Natural Plasmid Uniquely Encodes Two Biosynthetic Pathways Creating a Potent Anti-MRSA Antibiotic. In: PLoS ONE. 2011 ; Vol. 6, No. 3. pp. e18031.

Bibtex

@article{c60c3da0714546b9879d2e40daadbf8b,
title = "A Natural Plasmid Uniquely Encodes Two Biosynthetic Pathways Creating a Potent Anti-MRSA Antibiotic.",
abstract = "Background Understanding how complex antibiotics are synthesised by their producer bacteria is essential for creation of new families of bioactive compounds. Thiomarinols, produced by marine bacteria belonging to the genus Pseudoalteromonas, are hybrids of two independently active species: the pseudomonic acid mixture, mupirocin, which is used clinically against MRSA, and the pyrrothine core of holomycin. Methodology/Principal Findings High throughput DNA sequencing of the complete genome of the producer bacterium revealed a novel 97 kb plasmid, pTML1, consisting almost entirely of two distinct gene clusters. Targeted gene knockouts confirmed the role of these clusters in biosynthesis of the two separate components, pseudomonic acid and the pyrrothine, and identified a putative amide synthetase that joins them together. Feeding mupirocin to a mutant unable to make the endogenous pseudomonic acid created a novel hybrid with the pyrrothine via “mutasynthesis” that allows inhibition of mupirocin-resistant isoleucyl-tRNA synthetase, the mupirocin target. A mutant defective in pyrrothine biosynthesis was also able to incorporate alternative amine substrates. Conclusions/Significance Plasmid pTML1 provides a paradigm for combining independent antibiotic biosynthetic pathways or using mutasynthesis to develop a new family of hybrid derivatives that may extend the effective use of mupirocin against MRSA.",
author = "D Fukuda and Anthony Haines and Z Song and AC Murphy and Joanne Hothersall and Elton Stephens and Rachel Gurney and RJ Cox and J Crosby and CL Willis and TJ Simpson and Christopher Thomas",
year = "2011",
month = jan,
day = "1",
doi = "10.1371/journal.pone.0018031",
language = "English",
volume = "6",
pages = "e18031",
journal = "PLoSONE",
issn = "1932-6203",
publisher = "Public Library of Science (PLOS)",
number = "3",

}

RIS

TY - JOUR

T1 - A Natural Plasmid Uniquely Encodes Two Biosynthetic Pathways Creating a Potent Anti-MRSA Antibiotic.

AU - Fukuda, D

AU - Haines, Anthony

AU - Song, Z

AU - Murphy, AC

AU - Hothersall, Joanne

AU - Stephens, Elton

AU - Gurney, Rachel

AU - Cox, RJ

AU - Crosby, J

AU - Willis, CL

AU - Simpson, TJ

AU - Thomas, Christopher

PY - 2011/1/1

Y1 - 2011/1/1

N2 - Background Understanding how complex antibiotics are synthesised by their producer bacteria is essential for creation of new families of bioactive compounds. Thiomarinols, produced by marine bacteria belonging to the genus Pseudoalteromonas, are hybrids of two independently active species: the pseudomonic acid mixture, mupirocin, which is used clinically against MRSA, and the pyrrothine core of holomycin. Methodology/Principal Findings High throughput DNA sequencing of the complete genome of the producer bacterium revealed a novel 97 kb plasmid, pTML1, consisting almost entirely of two distinct gene clusters. Targeted gene knockouts confirmed the role of these clusters in biosynthesis of the two separate components, pseudomonic acid and the pyrrothine, and identified a putative amide synthetase that joins them together. Feeding mupirocin to a mutant unable to make the endogenous pseudomonic acid created a novel hybrid with the pyrrothine via “mutasynthesis” that allows inhibition of mupirocin-resistant isoleucyl-tRNA synthetase, the mupirocin target. A mutant defective in pyrrothine biosynthesis was also able to incorporate alternative amine substrates. Conclusions/Significance Plasmid pTML1 provides a paradigm for combining independent antibiotic biosynthetic pathways or using mutasynthesis to develop a new family of hybrid derivatives that may extend the effective use of mupirocin against MRSA.

AB - Background Understanding how complex antibiotics are synthesised by their producer bacteria is essential for creation of new families of bioactive compounds. Thiomarinols, produced by marine bacteria belonging to the genus Pseudoalteromonas, are hybrids of two independently active species: the pseudomonic acid mixture, mupirocin, which is used clinically against MRSA, and the pyrrothine core of holomycin. Methodology/Principal Findings High throughput DNA sequencing of the complete genome of the producer bacterium revealed a novel 97 kb plasmid, pTML1, consisting almost entirely of two distinct gene clusters. Targeted gene knockouts confirmed the role of these clusters in biosynthesis of the two separate components, pseudomonic acid and the pyrrothine, and identified a putative amide synthetase that joins them together. Feeding mupirocin to a mutant unable to make the endogenous pseudomonic acid created a novel hybrid with the pyrrothine via “mutasynthesis” that allows inhibition of mupirocin-resistant isoleucyl-tRNA synthetase, the mupirocin target. A mutant defective in pyrrothine biosynthesis was also able to incorporate alternative amine substrates. Conclusions/Significance Plasmid pTML1 provides a paradigm for combining independent antibiotic biosynthetic pathways or using mutasynthesis to develop a new family of hybrid derivatives that may extend the effective use of mupirocin against MRSA.

U2 - 10.1371/journal.pone.0018031

DO - 10.1371/journal.pone.0018031

M3 - Article

C2 - 21483852

VL - 6

SP - e18031

JO - PLoSONE

JF - PLoSONE

SN - 1932-6203

IS - 3

ER -