PDF(Pubmed)
Abstract：
Tuberculosis (TB) caused by bacteria of the Mycobacterium tuberculosis complex remains one of the most important infectious diseases of mankind. Rifampicin is a first line drug used in multi-drug treatment of TB, however, the necessary duration of treatment with these drugs is long and development of resistance is an increasing impediment to treatment programmes. As a result, there is a requirement for research and development of new TB drugs, which can form the basis of new drug combinations, either due to their own anti-mycobacterial activity or by augmenting the activity of existing drugs such as rifampicin. This study describes a TnSeq analysis to identify mutants with enhanced sensitivity to sub-minimum inhibitory concentrations (MIC) of rifampicin. The rifampicin-sensitive mutants were disrupted in genes of a variety of functions and the majority fitted into three thematic groups: firstly, genes that were involved in DNA/RNA metabolism, secondly, genes involved in sensing and regulating mycobacterial cellular systems, and thirdly, genes involved in the synthesis and maintenance of the cell wall. Selection at two concentrations of rifampicin (1/250 and 1/62 MIC) demonstrated a dose response for mutants with statistically significant sensitivity to rifampicin. The dataset reveals mechanisms of how mycobacteria are innately tolerant to and initiate an adaptive response to rifampicin; providing putative targets for the development of adjunctive therapies that potentiate the action of rifampicin.
摘要：
由结核分枝杆菌复合体的细菌引起的结核病（TB）仍然是人类最重要的传染病之一。利福平是用于结核病多药治疗的一线药物，然而,这些药物治疗的必要持续时间很长，耐药性的发展越来越阻碍治疗计划。因此,需要研发新的结核病药物，这可以构成新药组合的基础，由于它们自身的抗分枝杆菌活性或通过增加现有药物如利福平的活性。这项研究描述了TnSeq分析，以鉴定对利福平的亚最低抑制浓度（MIC）具有增强敏感性的突变体。对利福平敏感的突变体在具有多种功能的基因中被破坏，大多数适合三个主题组：首先，参与DNA/RNA代谢的基因，其次,参与感知和调节分枝杆菌细胞系统的基因，第三，参与细胞壁合成和维持的基因。在两种浓度的利福平(1/250和1/62MIC)下的选择证明了对利福平具有统计学显著敏感性的突变体的剂量响应。该数据集揭示了分枝杆菌如何天生耐受利福平并启动对利福平的适应性反应的机制；为开发增强利福平作用的辅助疗法提供了假定的目标。
