Dysregulation of mprF and dltABCD expression among daptomycin-non-susceptible MRSA clinical isolates
Dysregulation of mprF and dltABCD expression among daptomycin-non-susceptible MRSA clinical isolates
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DOI：
10.1093/jac/dkw142
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发表时间：
2016-08-01
影响因子：
5.2
通讯作者：
Yang, Soo-Jin
中科院分区：
文献类型：
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作者：
Bayer, Arnold S.;Mishra, Nagendra N.;Yang, Soo-Jin
在小系列或个别报道中，mprF ORF中的SNPs及其在金黄色葡萄球菌中表达的失调与达托霉素耐药(DAP-R)有关，这是一种已提出的功能增益机制。同样，dltABCD的调节失调也与DAP-R有关。使用22对特征良好的等基因达托霉素敏感株(DAP-S)/DAP-R临床MRSA菌株，我们评估了DAP-R表型与以下因素的潜在关系：(I)mprF转录的调节；(Ii)dltABCD转录的调节；(Iii)两组分调节系统的表达，graRS(mprF和dltABCD转录的上游调节因子)；(Iv)graRS启动子或其ORF内的SNP；和(V)改变mprF的转录和赖氨酰磷脂酰甘油(L-PG)的合成。mprF的表达增强与SNPs一起发生在高度不同和记录良好的MprF结构域的‘热点’中，很少没有这样的突变。MprF和dltABCD的表达增加和/或失调在DAP-R菌株中并不少见，每种基因都有27%的菌株发生。在这些菌株中，graRS表达谱或graRS启动子或ORF内的多态序列都不能显著地与mprF或dlt转录的改变相关联。虽然graRS可以共同调节mprF和dltABCD的表达，但该调控子外的基因似乎与后两个基因和DAP-R表型的失调有关。最后，mprF转录谱显著改变的DAP-R菌株产生显著增加的L-PG水平。
In small series or individual reports, SNPs within the mprF ORF and dysregulation of its expression in Staphylococcus aureus have been linked to daptomycin resistance (DAP-R) via a proposed gain-in-function mechanism. Similarly, dysregulation of dltABCD has also been associated with DAP-R.Using 22 well-characterized, isogenic daptomycin-susceptible (DAP-S)/DAP-R clinical MRSA strain pairs, we assessed potential relationships of the DAP-R phenotype with: (i) regulation of mprF transcription; (ii) regulation of dltABCD transcription; (iii) expression of the two-component regulatory system, graRS (upstream regulator for both mprF and dltABCD transcription); (iv) SNPs within the graRS promoter or its ORF; and (v) altered mprF transcription and lysyl-phosphatidylglycerol (L-PG) synthesis.Enhanced expression of mprF occurred with SNPs in highly distinct and well-chronicled MprF domain 'hot spots' and rarely occurred without such mutations. Increased expression and/or dysregulation of mprF and dltABCD were not uncommon in DAP-R strains, occurring in 27% of strains for each gene. In these latter strains, neither graRS expression profiles nor polymorphic sequences within the graRS promoter or ORF could be significantly linked to altered transcription of mprF or dlt.Although graRS can co-regulate mprF and dltABCD expression, loci outside of this regulon appear to be involved in dysregulation of these latter two genes and the DAP-R phenotype. Finally, DAP-R strains exhibiting significantly altered mprF transcription profiles produced significantly increased levels of L-PG.