Key Laboratory of Medical Molecular Virology, Institutes of Biomedical Sciences and Institute of Medical Microbiology, Fudan University, Shanghai, China.
J Infect Dis. 2012 Dec 1;206(11):1724-33. doi: 10.1093/infdis/jis601. Epub 2012 Sep 14.
Drug-resistant tuberculosis poses a growing challenge to global public health. However, the diversity and dynamics of the bacterial population during acquisition of drug resistance have yet to be carefully examined.
Whole-genome sequencing was performed on 7 serial Mycobacterium tuberculosis (M. tuberculosis) populations from 3 patients during different stages in the development of drug resistance. The population diversity was assessed by the number and frequencies of unfixed mutations in each sample.
For each bacterial population, 8-41 unfixed mutations were monitored by the fraction of single-nucleotide polymorphisms at specific loci. Among them, as many as 4 to 5 resistance-conferring mutations were transiently detected in the same single sputum, but ultimately only a single type of mutant was fixed. In addition, we identified 14 potential compensatory mutations that occurred during or after the emergence of resistance-conferring mutations.
M. tuberculosis population within patients exhibited considerable genetic diversity, which underwent selections for most fit resistant mutant. These findings have important implications and emphasize the need for early diagnosis of tuberculosis to decrease the chance of evolving highly fit drug-resistant strains.
耐药结核病对全球公共卫生构成日益严峻的挑战。然而，细菌在获得耐药性过程中的多样性和动态变化尚未得到仔细研究。
对 3 名患者在耐药性发展的不同阶段的 7 个连续结核分枝杆菌（M. tuberculosis）种群进行全基因组测序。通过每个样本中固定突变的数量和频率评估种群多样性。
对于每个细菌种群，通过特定位点的单核苷酸多态性分数监测 8-41 个未固定突变。其中，多达 4 到 5 种耐药性突变在同一痰标本中被短暂检测到，但最终只有一种突变被固定。此外，我们还鉴定出 14 种潜在的补偿性突变，这些突变发生在耐药性突变出现期间或之后。
患者体内的结核分枝杆菌种群表现出相当大的遗传多样性，经过选择后最适合的耐药突变体得以保留。这些发现具有重要意义，强调了早期诊断结核病的必要性，以降低产生高度适应的耐药菌株的机会。
