Emergence of vancomycin tolerance in Streptococcus pneumoniae
Emergence of vancomycin tolerance in Streptococcus pneumoniae
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DOI：
10.1038/21202
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发表时间：
1999-06-10
期刊：
影响因子：
64.8
通讯作者：
Tuomanen, E
中科院分区：
文献类型：
--
作者：
Novak, R;Henriques, B;Tuomanen, E
肺炎链球菌，即肺炎球菌，是导致败血症和脑膜炎的最常见原因(1)。多重耐药菌株广泛存在，万古霉素是最后的抗生素（2,3）。在这种社区获得性细菌中出现万古霉素耐药性将是灾难性的。抗生素耐受性，即细菌在抗生素存在下存活但不生长的能力，是耐药性的前兆表型(4)。在这里，我们发现肺炎链球菌双组分传感器调节系统的VncS组氨酸激酶功能的丧失产生了对万古霉素和其他种类抗生素的耐受性。细菌双组分系统通过传感器组氨酸激酶/磷酸酶监测环境参数，该传感器磷酸化/去磷酸化反应调节因子，进而介导基因表达的变化。这些结果表明，信号转导对抗生素的杀菌活性至关重要。由vnc突变体引起的实验性脑膜炎对万古霉素没有反应。鉴定出对万古霉素耐受的临床分离株，DNA测序显示vnc的核苷酸改变。我们得出结论，肺炎链球菌广泛的抗生素耐受性已经在社区中出现，通过分子机制消除了对目前治疗万古霉素的敏感性。
Streptococcus pneumoniae, the pneumococcus, is the most common cause of sepsis and meningitis(1). Mwultiple-antibiotic-resistant strains are widespread, and vancomycin is the antibiotic of last resort(2,3). Emergence of vancomycin resistance In this community-acquired bacterium would be catastrophic. Antibiotic tolerance, the ability of bacteria to survive but not grow in the presence of antibiotics, is a precursor phenotype to resistance(4) Here we show that loss of function of the VncS histidine kinase of a two-component sensor-regulator system in S. pneumoniae produced tolerance to vancomycin and other classes of antibiotic. Bacterial two-component systems monitor environmental parameters through a sensor histidine-kinase/phosphatase, which phosphorylates/dephosphorylates a response regulator that in turn mediates changes in gene expression. These results indicate that signal transduction is critical for the bactericidal activity of antibiotics. Experimental meningitis caused by the vncS mutant failed to respond to vancomycin. Clinical isolates tolerant to vancomycin were identified and DNA sequencing revealed nucleotide alterations in vncS. We conclude that broad antibiotic tolerance of S. pneumoniae has emerged in the community by a molecular mechanism that eliminates sensitivity to the current cornerstone of therapy vancomycin.