Details
| Originalsprache | Englisch |
|---|---|
| Aufsatznummer | e18031 |
| Fachzeitschrift | PLOS ONE |
| Jahrgang | 6 |
| Ausgabenummer | 3 |
| Publikationsstatus | Veröffentlicht - 7 Apr. 2011 |
| Extern publiziert | Ja |
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.
ASJC Scopus Sachgebiete
- Biochemie, Genetik und Molekularbiologie (insg.)
- Allgemeine Biochemie, Genetik und Molekularbiologie
- Agrar- und Biowissenschaften (insg.)
- Allgemeine Agrar- und Biowissenschaften
- Allgemein
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in: PLOS ONE, Jahrgang 6, Nr. 3, e18031, 07.04.2011.
Publikation: Beitrag in Fachzeitschrift › Artikel › Forschung › Peer-Review
}
TY - JOUR
T1 - A natural plasmid uniquely encodes two biosynthetic pathways creating a potent anti-MRSA antibiotic
AU - Fukuda, Daisuke
AU - Haines, Anthony S.
AU - Song, Zhongshu
AU - Murphy, Annabel C.
AU - Hothersall, Joanne
AU - Stephens, Elton R.
AU - Gurney, Rachel
AU - Cox, Russell J.
AU - Crosby, John
AU - Willis, Christine L.
AU - Simpson, Thomas J.
AU - Thomas, Christopher M.
N1 - Funding information: This work was funded by a grant from the UK Research Councils BBSRC and EPSRC. Daisuke Fukuda was still an employee of the company Daiichi-Sankyo while he was seconded to the University of Birmingham.
PY - 2011/4/7
Y1 - 2011/4/7
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.
UR - http://www.scopus.com/inward/record.url?scp=79953309108&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0018031
DO - 10.1371/journal.pone.0018031
M3 - Article
C2 - 21483852
AN - SCOPUS:79953309108
VL - 6
JO - PLOS ONE
JF - PLOS ONE
SN - 1932-6203
IS - 3
M1 - e18031
ER -