A natural plasmid uniquely encodes two biosynthetic pathways creating a potent anti-MRSA antibiotic.
A natural plasmid uniquely encodes two biosynthetic pathways creating a potent anti-MRSA antibiotic.
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DOI：
10.1371/journal.pone.0018031
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发表时间：
2011-03-31
期刊：
影响因子：
3.7
通讯作者：
Thomas CM
中科院分区：
文献类型：
--
作者：
Fukuda D;Haines AS;Song Z;Murphy AC;Hothersall J;Stephens ER;Gurney R;Cox RJ;Crosby J;Willis CL;Simpson TJ;Thomas CM
了解复杂的抗生素是如何由其生产细菌合成的，对于创造新的生物活性化合物家族至关重要。由属于假交替单胞菌属的海洋细菌产生的硫代马里诺是两种独立活性物种的杂交种：假单胞菌酸混合物，莫匹罗星，其在临床上用于对抗MRSA，以及全霉素的吡咯核心。生产细菌的全基因组的高通量DNA测序揭示了一种新的97 kb质粒pTML 1，几乎完全由两个不同的基因簇组成。靶向基因敲除证实了这些簇在两个单独组分假单胞菌酸和吡咯硫的生物合成中的作用，并鉴定了将它们连接在一起的推定的酰胺合成酶。将莫匹罗星喂给不能产生内源性假单胞菌酸的突变体，通过“突变合成”与吡咯烷酮产生了一种新的杂合物，该杂合物允许抑制莫匹罗星耐药的异亮氨酰-tRNA合成酶，即莫匹罗星靶点。吡咯合成缺陷的突变体也能够纳入替代胺底物。质粒pTML 1提供了一个范例，用于组合独立的抗生素生物合成途径或使用突变合成来开发一个新的杂交衍生物家族，该杂交衍生物家族可以扩展莫匹罗星对MRSA的有效使用。
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. 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. 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.
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