Increased Cell Wall Teichoic Acid Production and D-alanylation Are Common Phenotypes among Daptomycin-Resistant Methicillin-Resistant Staphylococcus aureus (MRSA) Clinical Isolates
Increased Cell Wall Teichoic Acid Production and D-alanylation Are Common Phenotypes among Daptomycin-Resistant Methicillin-Resistant Staphylococcus aureus (MRSA) Clinical Isolates
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DOI：
10.1371/journal.pone.0067398
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发表时间：
2013-06-13
期刊：
影响因子：
3.7
通讯作者：
Weidenmaier, Christopher
中科院分区：
文献类型：
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作者：
Bertsche, Ute;Yang, Soo-Jin;Weidenmaier, Christopher
金黄色葡萄球菌的达托霉素耐药性（DAP-R）与多种机制相关。然而，在许多DAP-RS中观察到一个共同的表型。金黄色菌株是一个增厚的细胞壁（CW）。最近，在一个单一的，充分表征的DAP-R甲氧西林敏感性S。金黄色葡萄球菌（MSSA）菌株。在该分离株中，增厚的CW表型与壁磷壁酸（WTA）的产生和D-丙氨酰化增加有关。在本报告中，我们将这些观察结果扩展到甲氧西林耐药达托霉素敏感/达托霉素耐药（DAP-S/DAP-R）菌株对。这些对包括耐甲氧西林的S。金黄色葡萄球菌（MRSA）分离株在mprF（与DAP-R表型连锁的遗传基因座）中具有和不具有单核苷酸多态性（SNP）。我们发现所有DAP-R与DAP-S分离株的CW干重增加。这与WTA生物合成基因tagA的表达增加以及DAP-R与DAP-S分离株中WTA的量增加相关。此外，所有DAP-R分离株均显示出比其相应DAP-S分离株更高的WTA D-丙氨酰化比例。我们还在DAP-R菌株中检测到增加的正表面电荷（推测与增强的D-丙氨酰化有关）。在比较所有分离物对的详细CW组成时，仅在一个DAP-S/DAP-R对中检测到实质性差异。增厚的CW表型连同增加的表面电荷最有可能促成：i）钙络合的DAP的电荷依赖性排斥;和/或ii）DAP对细菌细胞包膜靶标的空间受限接近。总之，CW结构和功能指标的明确扰动有助于DAP-R表型，并且是DAP-RS中常见的表型。注意：虽然“达托霉素不敏感”是普遍接受的术语，但为了便于在本文中介绍，我们使用了“达托霉素耐药”这一术语
Multiple mechanisms have been correlated with daptomycin-resistance (DAP-R) in Staphylococcus aureus. However, one common phenotype observed in many DAP-R S. Aureus strains is a thickened cell wall (CW). The first evidence for an impact of CW-linked glycopolymers on this phenotype was recently demonstrated in a single, well-characterized DAP-R methicillin-susceptible S. aureus (MSSA) strain. In this isolate the thickened CW phenotype was linked to an increased production and D-alanylation of wall teichoic acids (WTA). In the current report, we extended these observations to methicillin-resistant daptomycin-sensitive/daptomyin-resistant (DAP-S/DAP-R) strain-pairs. These pairs included methicillin-resistant S. aureus (MRSA) isolates with and without single nucleotide polymorphisms (SNPs) in mprF (a genetic locus linked to DAP-R phenotype). We found increased CW dry mass in all DAP-R vs DAP-S isolates. This correlated with an increased expression of the WTA biosynthesis gene tagA, as well as an increased amount of WTA in the DAP-R vs DAP-S isolates. In addition, all DAP-R isolates showed a higher proportion of WTA D-alanylation vs their corresponding DAP-S isolate. We also detected an increased positive surface charge amongst the DAP-R strains (presumably related to the enhanced D-alanylation). In comparing the detailed CW composition of all isolate pairs, substantive differences were only detected in one DAP-S/DAP-R pair. The thickened CW phenotype, together with an increased surface charge most likely contributes to either: i) a charge-dependent repulsion of calcium complexed-DAP; and/or ii) steric-limited access of DAP to the bacterial cell envelope target. Taken together well-defined perturbations of CW structural and functional metrics contribute to the DAP-R phenotype and are common phenotypes in DAP-R S. Aureus isolates, both MSSA and MRSA.Note: Although "daptomycin-nonsusceptibility" is the generally accepted terminology, we have utilized the term "daptomycin resistance" for ease of presentation in this manuscript