Identification of the biosynthetic gene cluster and an additional gene for resistance to the antituberculosis drug capreomycin
Identification of the biosynthetic gene cluster and an additional gene for resistance to the antituberculosis drug capreomycin
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DOI：
10.1128/aem.00485-07
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发表时间：
2007-07-01
影响因子：
4.4
通讯作者：
Thomas, Michael G.
中科院分区：
文献类型：
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作者：
Felnagle, Elizabeth A.;Rondon, Michelle R.;Thomas, Michael G.
卷曲霉素（CMN）属于结核放线菌素家族的非核糖体肽抗生素，是治疗多药耐药结核病的药物库的重要组成部分。这种抗生素家族的成员以敏感细菌的核糖体为目标，破坏核糖体的两个亚基的功能。分枝杆菌对这些抗生素的耐药性是由于编码16S或23S rRNA的基因突变引起的，但也可能是由于编码rRNA修饰酶TlyA的基因突变引起的。虽然分枝杆菌由于药物靶点的改变而产生耐药性，但已经提出产生cmn的细菌Saccharothix mutabilis subsp。capreolus使用CMN修饰而不是核糖体修饰作为耐药机制。为了更好地了解变异链球菌亚种CMN的生物合成和耐药性。我们重点鉴定了该细菌的CMN生物合成基因簇。本文报道了s.a mutabilis亚种CMN生物合成基因簇的克隆和序列分析。capreolus ATCC 23892。我们为在遗传易感的lividans链霉菌1326中异源产生CMN提供了证据。最后，我们提出的数据支持另外一个CMN抗性基因的存在。最初的研究表明，这种耐药基因编码一种rna修饰酶，导致cmn耐药核糖体的形成，这种核糖体也对氨基糖苷类抗生素卡那霉素耐药。因此，变异葡萄球菌亚种。毛豆也可能利用核糖体修饰作为CMN抗性的机制。
Capreomycin (CMN) belongs to the tuberactinomycin family of nonribosomal peptide antibiotics that are essential components of the drug arsenal for the treatment of multidrug-resistant tuberculosis. Members of this antibiotic family target the ribosomes of sensitive bacteria and disrupt the function of both subunits of the ribosome. Resistance to these antibiotics in Mycobacterium species arises due to mutations in the genes coding for the 16S or 23S rRNA but can also arise due to mutations in a gene coding for an rRNA-modifying enzyme, TlyA. While Mycobacterium species develop resistance due to alterations in the drug target, it has been proposed that the CMN-producing bacterium, Saccharothix mutabilis subsp. capreolus, uses CMN modification as a mechanism for resistance rather than ribosome modification. To better understand CMN biosynthesis and resistance in S. mutabilis subsp. capreolus, we focused on the identification of the CMN biosynthetic gene cluster in this bacterium. Here, we describe the cloning and sequence analysis of the CMN biosynthetic gene cluster from S. mutabilis subsp. capreolus ATCC 23892. We provide evidence for the heterologous production of CMN in the genetically tractable bacterium Streptomyces lividans 1326. Finally, we present data supporting the existence of an additional CMN resistance gene. Initial work suggests that this resistance gene codes for an rRNA-modifying enzyme that results in the formation of CMN-resistant ribosomes that are also resistant to the aminoglycoside antibiotic kanamycin. Thus, S. mutabilis subsp. capreolus may also use ribosome modification as a mechanism for CMN resistance.