PhoY2 而非 PhoY1 是分枝杆菌中与持久菌相关的 PhoU 同源物。
PhoY2 but not PhoY1 is the PhoU homologue involved in persisters in Mycobacterium tuberculosis.
机构信息
Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA.
出版信息
J Antimicrob Chemother. 2010 Jun;65(6):1237-42. doi: 10.1093/jac/dkq103. Epub 2010 Apr 1.
OBJECTIVES
Mycobacterial persistence is thought to be the underlying cause of the current lengthy tuberculosis therapy and latent infection. Despite some recent progress, the mechanisms of bacterial persistence are poorly understood. We have recently identified a new persister gene phoU from Escherichia coli and have shown that the phoU mutant has a defect in persisters. The objective of this study is to evaluate the role of two phoU homologues phoY1 and phoY2 from Mycobacterium tuberculosis in mycobacterial persistence.
METHODS
M. tuberculosis phoY1 and phoY2 mutant strains were constructed. The persister-related phenotypes of the phoY1 and phoY2 mutants were assessed in vitro by MIC testing, drug exposure assays and also by survival in the mouse model of tuberculosis infection.
RESULTS
We demonstrated that M. tuberculosis PhoY2 is the equivalent of E. coli PhoU in that inactivation of phoY2 but not phoY1 caused a defect in persistence phenotype as shown by increased susceptibility to rifampicin and pyrazinamide in both MIC testing and drug exposure assays and also reduced persistence in the mouse model.
CONCLUSIONS
This study provides further validation that PhoU is involved in persistence not only in E. coli but also in M. tuberculosis and has implications for the development of new drugs targeting persisters for improved treatment.
目的
分枝杆菌的持续存在被认为是目前结核病治疗时间长和潜伏感染的根本原因。尽管最近取得了一些进展，但细菌持续存在的机制仍知之甚少。我们最近从大肠杆菌中鉴定出一种新的持续生存基因 phoU，并表明 phoU 突变体在持续生存方面存在缺陷。本研究的目的是评估分枝杆菌 phoY1 和 phoY2 两种同源物在分枝杆菌持续存在中的作用。
方法
构建了结核分枝杆菌 phoY1 和 phoY2 突变株。通过 MIC 试验、药物暴露试验以及在结核分枝杆菌感染小鼠模型中的存活情况，评估了 phoY1 和 phoY2 突变体的持续生存相关表型。
结果
我们证明，结核分枝杆菌 PhoY2 相当于大肠杆菌 PhoU，因为 phoY2 的失活而不是 phoY1 的失活导致了持续生存表型的缺陷，表现在 MIC 试验和药物暴露试验中对利福平和顺铂的敏感性增加，以及在小鼠模型中持续生存能力降低。
结论
这项研究进一步验证了 PhoU 不仅参与了大肠杆菌的持续生存，也参与了结核分枝杆菌的持续生存，这对开发针对持续生存菌的新药物以改善治疗具有重要意义。
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