A naturally occurring gene amplification leading to sulfonamide and trimethoprim resistance in Streptococcus agalactiae
A naturally occurring gene amplification leading to sulfonamide and trimethoprim resistance in Streptococcus agalactiae
复制标题
DOI：
10.1128/jb.01357-07
复制
发表时间：
2008-01-01
影响因子：
3.2
通讯作者：
Glaser, Philippe
中科院分区：
文献类型：
--
作者：
Brochet, Mathieu;Couve, Elisabeth;Glaser, Philippe
基因扩增已被检测为细菌培养物中的短暂现象。预计它们将通过同时增加染色体上聚集的基因的表达来促进快速适应。然而，在自然分离株中很少描述基因组扩增。通过 DNA 阵列分析，我们鉴定了两种携带串联基因组扩增的无乳链球菌菌株：13.5 kb 的四倍扩增和 92 kb 的重复。两个扩增都位于靠近复制末端的位置，并且独立于任何长重复序列而起源。它们可能出现在人类宿主中并表现出不同的稳定性，13.5 kb 扩增以每代 0.003 次的频率丢失，92 kb 串联重复以每代 0.035 次的频率丢失。 13.5 kb 串联扩增携带二氢叶酸生物合成所需的五个基因，并导致甲氧苄啶 (TMP) 和磺酰胺 (SU) 耐药性。对 SU 的耐药性可能是由于二氢叶酸合酶（该抗生素的靶点）合成增加所致，而整个途径的扩增则导致了 TMP 耐药性。这揭示了一种新的 TMP 抗性机制，涉及二氢叶酸生物合成的增加。据我们所知，这是第一个报道的因细菌基因组扩增而自然产生抗生素耐药性的病例。 DNA 片段扩增的低稳定性表明它们在抗生素耐药性中的作用可能被低估了。
Gene amplifications have been detected as a transitory phenomenon in bacterial cultures. They are predicted to contribute to rapid adaptation by simultaneously increasing the expression of genes clustered on the chromosome. However, genome amplifications have rarely been described in natural isolates. Through DNA array analysis, we have identified two Streptococcus agalactiae strains carrying tandem genome amplifications: a fourfold amplification of 13.5 kb and a duplication of 92 kb. Both amplifications were located close to the terminus of replication and originated independently from any long repeated sequence. They probably arose in the human host and showed different stabilities, the 13.5-kb amplification being lost at a frequency of 0.003 per generation and the 92-kb tandem duplication at a frequency of 0.035 per generation. The 13.5-kb tandem amplification carried the five genes required for dihydrofolate biosynthesis and led to both trimethoprim (TMP) and sulfonamide (SU) resistance. Resistance to SU probably resulted from the increased synthesis of dihydropteroate synthase, the target of this antibiotic, whereas the amplification of the whole pathway was responsible for TMP resistance. This revealed a new mechanism of resistance to TMP involving an increased dihydrofolate biosynthesis. This is, to our knowledge, the first reported case of naturally occurring antibiotic resistance resulting from genome amplification in bacteria. The low stability of DNA segment amplifications suggests that their role in antibiotic resistance might have been underestimated.