TCA cycle-mediated generation of ROS is a key mediator for HeR-MRSA survival under β-lactam antibiotic exposure.
TCA cycle-mediated generation of ROS is a key mediator for HeR-MRSA survival under β-lactam antibiotic exposure.
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DOI：
10.1371/journal.pone.0099605
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Rosato AE
中科院分区：
文献类型：
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作者：
Rosato RR;Fernandez R;Paz LI;Singh CR;Rosato AE
耐甲氧西林金黄色葡萄球菌(MRSA)是一种主要的多重耐药病原体，导致人类几种难以治疗的感染。临床异型耐药(HER)MRSA菌株大多与持续感染有关，由混合细胞群体组成，其中包含低水平耐药(异型耐药HER)和高耐药水平(同源耐药HoR)的微生物。然而，对β-内酰胺介导的HER/HoR选择的充分理解仍有待完成。在以前的研究中，我们证明了在接触β-内酰胺类抗生素的过程中，HoR表型的获得依赖于两个关键因素：(1)sOS反应的激活，这是细菌对dna损伤的一个保守的调控网络，导致突变率增加；(2)适应性代谢变化将hER-mrSA的代谢重定向到三羧酸循环，以增加细胞壁合成的能量供应。在目前的工作中，我们发现这两个主要的机制成分是通过TCA循环介导的活性氧物种(ROS)的产生而联系在一起的，ROS的产生在时间上影响DNA的完整性，并触发SOS反应的激活，从而导致增强的突变。目前的工作带来了新的见解，在一个自然发生的模型中，ROS的产生在β-内酰胺类抗生素的耐药性发展中所起的作用，强调了细胞保护在HER-MRSA生存机制中的作用。
Methicillin-resistant Staphylococcus aureus (MRSA) is a major multidrug resistant pathogen responsible for several difficult-to-treat infections in humans. Clinical Hetero-resistant (HeR) MRSA strains, mostly associated with persistent infections, are composed of mixed cell populations that contain organisms with low levels of resistance (hetero-resistant HeR) and those that display high levels of drug resistance (homo-resistant HoR). However, the full understanding of β-lactam-mediated HeR/HoR selection remains to be completed. In previous studies we demonstrated that acquisition of the HoR phenotype during exposure to β-lactam antibiotics depended on two key elements: (1) activation of the SOS response, a conserved regulatory network in bacteria that is induced in response to DNA damage, resulting in increased mutation rates, and (2) adaptive metabolic changes redirecting HeR-MRSA metabolism to the tricarboxylic acid (TCA) cycle in order to increase the energy supply for cell-wall synthesis. In the present work, we identified that both main mechanistic components are associated through TCA cycle-mediated reactive oxygen species (ROS) production, which temporally affects DNA integrity and triggers activation of the SOS response resulting in enhanced mutagenesis. The present work brings new insights into a role of ROS generation on the development of resistance to β-lactam antibiotics in a model of natural occurrence, emphasizing the cytoprotective role in HeR-MRSA survival mechanism.
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