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首页> 美国卫生研究院文献>PLoS Pathogens >Two Novel Point Mutations in Clinical Staphylococcus aureus Reduce Linezolid Susceptibility and Switch on the Stringent Response to Promote Persistent Infection
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Two Novel Point Mutations in Clinical Staphylococcus aureus Reduce Linezolid Susceptibility and Switch on the Stringent Response to Promote Persistent Infection

机译：临床金黄色葡萄球菌的两个新的点突变降低了利奈唑胺的易感性并启动了严格的反应以促进持续感染

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Staphylococcus aureus frequently invades the human bloodstream, leading to life threatening bacteremia and often secondary foci of infection. Failure of antibiotic therapy to eradicate infection is frequently described; in some cases associated with altered S. aureus antimicrobial resistance or the small colony variant (SCV) phenotype. Newer antimicrobials, such as linezolid, remain the last available therapy for some patients with multi-resistant S. aureus infections. Using comparative and functional genomics we investigated the molecular determinants of resistance and SCV formation in sequential S. aureus isolates from a patient who had a persistent and recurrent S. aureus infection, after failed therapy with multiple antimicrobials, including linezolid. Two point mutations in key staphylococcal genes dramatically affected clinical behaviour of the bacterium, altering virulence and antimicrobial resistance. Most strikingly, a single nucleotide substitution in relA (SACOL1689) reduced RelA hydrolase activity and caused accumulation of the intracellular signalling molecule guanosine 3′, 5′-bis(diphosphate) (ppGpp) and permanent activation of the stringent response, which has not previously been reported in S. aureus. Using the clinical isolate and a defined mutant with an identical relA mutation, we demonstrate for the first time the impact of an active stringent response in S. aureus, which was associated with reduced growth, and attenuated virulence in the Galleria mellonella model. In addition, a mutation in rlmN (SACOL1230), encoding a ribosomal methyltransferase that methylates 23S rRNA at position A2503, caused a reduction in linezolid susceptibility. These results reinforce the exquisite adaptability of S. aureus and show how subtle molecular changes cause major alterations in bacterial behaviour, as well as highlighting potential weaknesses of current antibiotic treatment regimens.
机译：金黄色葡萄球菌经常侵入人的血液，导致威胁生命的菌血症，并常常成为继发感染的焦点。经常描述抗生素治疗无法根除感染。在某些情况下，与金黄色葡萄球菌的抗药性改变或小菌落变异（SCV）表型有关。对于一些多耐药金黄色葡萄球菌感染的患者，较新的抗菌药物（如利奈唑胺）仍然是最后一种可用的疗法。使用比较基因组和功能基因组学，我们研究了在患有多种抗生素（包括利奈唑胺）治疗失败后，患有持续性和反复性金黄色葡萄球菌感染的患者的连续金黄色葡萄球菌分离株中耐药性和SCV形成的分子决定因素。关键葡萄球菌基因中的两个点突变极大地影响了细菌的临床行为，改变了毒力和抗药性。最为显着的是，relA（SACOL1689）中的单个核苷酸取代降低了RelA水解酶的活性，并导致细胞内信号分子鸟苷3'，5'-双（二磷酸）（ppGpp）的积累和严格应答的永久激活，这是以前从未有过的在金黄色葡萄球菌中有报道。使用临床分离株和具有相同relA突变的已定义突变体，我们首次证明了金黄色葡萄球菌中主动严格应答的影响，该反应与降低的生长和在马勒菌廊模型中的毒力减弱有关。此外，rlmN（SACOL1230）的突变编码一个核糖体甲基转移酶，使A2503位置的23S rRNA甲基化，导致利奈唑胺敏感性降低。这些结果增强了金黄色葡萄球菌的出色适应性，并显示出细微的分子变化如何引起细菌行为的重大改变，并突出了当前抗生素治疗方案的潜在弱点。

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