The Cell Wall Polymer Lipoteichoic Acid Becomes Nonessential in Staphylococcus aureus Cells Lacking the ClpX Chaperone.
The Cell Wall Polymer Lipoteichoic Acid Becomes Nonessential in Staphylococcus aureus Cells Lacking the ClpX Chaperone.
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DOI：
10.1128/mbio.01228-16
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发表时间：
2016-08-09
期刊：
影响因子：
6.4
通讯作者：
Frees D
中科院分区：
文献类型：
--
作者：
Bæk KT;Bowman L;Millership C;Dupont Søgaard M;Kaever V;Siljamäki P;Savijoki K;Varmanen P;Nyman TA;Gründling A;Frees D
脂磷胆酸（LTA）是革兰氏阳性细菌的重要细胞壁成分，也是开发金黄色葡萄球菌疫苗和抗菌化合物的一个有希望的靶点。在这里，我们证明了条件必需ltaS （LTA合成酶）基因的突变在缺乏ClpX伴侣的金黄色葡萄球菌突变体中自发发生。各种各样的ltaS突变被选择，其中很大一部分导致过早终止密码子和其他预测会终止ltaS合成的变化。与这一假设一致，clpX ltaS双突变体不产生LTA，遗传分析证实，在缺乏clpX伴侣的情况下，LTA变得不重要。事实上，ltaS的失活减轻了clpX缺失带来的严重生长缺陷。显微镜分析显示，ClpX的缺失部分缓解了lta缺失菌株的隔膜放置缺陷，而lta阴性金黄色葡萄球菌突变体的其他典型表型，包括细胞大小增加和自溶活性降低，仍被保留。总之，我们的研究结果表明LTA在隔膜放置中具有重要作用，可以通过使ClpX伴侣失活来绕过隔膜放置。脂磷胆酸是金黄色葡萄球菌细胞包膜的重要组成部分，也是开发针对耐甲氧西林金黄色葡萄球菌和万古霉素耐肠球菌等耐抗生素革兰氏阳性细菌的疫苗和抗菌剂的有吸引力的靶标。在这项研究中，我们发现，只要细胞中存在ClpX伴侣，脂磷胆酸聚合物对金黄色葡萄球菌的生长是必不可少的。我们的研究结果表明，脂壁酸和ClpX在金黄色葡萄球菌控制两个关键细胞分裂过程，即隔膜形成和自溶活性的途径中发挥相反的作用。在控制金黄色葡萄球菌细胞分裂的遗传网络中发现一种新的功能联系，可能会扩大鉴定杀死耐抗生素金黄色葡萄球菌的化合物或化合物组合的可能策略。
Lipoteichoic acid (LTA) is an important cell wall component of Gram-positive bacteria and a promising target for the development of vaccines and antimicrobial compounds against Staphylococcus aureus. Here we demonstrate that mutations in the conditionally essential ltaS (LTA synthase) gene arise spontaneously in an S. aureus mutant lacking the ClpX chaperone. A wide variety of ltaS mutations were selected, and among these, a substantial portion resulted in premature stop codons and other changes predicted to abolish LtaS synthesis. Consistent with this assumption, the clpX ltaS double mutants did not produce LTA, and genetic analyses confirmed that LTA becomes nonessential in the absence of the ClpX chaperone. In fact, inactivation of ltaS alleviated the severe growth defect conferred by the clpX deletion. Microscopic analyses showed that the absence of ClpX partly alleviates the septum placement defects of an LTA-depleted strain, while other phenotypes typical of LTA-negative S. aureus mutants, including increased cell size and decreased autolytic activity, are retained. In conclusion, our results indicate that LTA has an essential role in septum placement that can be bypassed by inactivating the ClpX chaperone. Lipoteichoic acid is an essential component of the Staphylococcus aureus cell envelope and an attractive target for the development of vaccines and antimicrobials directed against antibiotic-resistant Gram-positive bacteria such as methicillin-resistant S. aureus and vancomycin-resistant enterococci. In this study, we showed that the lipoteichoic acid polymer is essential for growth of S. aureus only as long as the ClpX chaperone is present in the cell. Our results indicate that lipoteichoic acid and ClpX play opposite roles in a pathway that controls two key cell division processes in S. aureus, namely, septum formation and autolytic activity. The discovery of a novel functional connection in the genetic network that controls cell division in S. aureus may expand the repertoire of possible strategies to identify compounds or compound combinations that kill antibiotic-resistant S. aureus.