DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research, SA MRC Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, PO Box 19063, Tygerberg, Cape Town, 7505, South Africa.
Tuberculosis Omics Research Consortium, Family Medicine and Population Health, Institute of Global Health, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.
Sci Rep. 2024 Nov 12;14(1):27686. doi: 10.1038/s41598-024-79389-w.
Current tuberculosis (TB) treatment is typically effective against drug-susceptible Mycobacterium tuberculosis, but can fail due to acquired drug resistance or phenotypic resistance. M. tuberculosis persisters, a subpopulation of viable but non-replicating (VBNR) antibiotic-tolerant bacteria, are thought to contribute to poor TB treatment outcomes. In this exploratory study, we investigated treatment-naïve drug-susceptible clinical isolates collected from people with TB, who subsequently had unsuccessful treatment outcomes. These were compared to isolates from cured individuals in terms of their ability to form VBNR subpopulations. Clinical isolates from individuals with unfavorable treatment outcomes form larger subpopulations of VBNR M. tuberculosis (2.67-13.71%) than clinical isolates from cured cases (0- 1.63%) following infection of THP-1 macrophages. All isolates were drug susceptible based on phenotypic and genotypic analysis. Whole genome sequencing identified 23 non-synonymous genomic variants shared by treatment failure clinical isolates, that were not present in isolates from cured cases. This exploratory study highlights the ability of treatment-naïve clinical isolates to form heterogeneous populations containing VBNR M. tuberculosis. We also demonstrate that clinical isolates from individuals with unsuccessful treatment outcomes form higher percentages of VBNR M. tuberculosis. The findings of this exploratory study suggest that an increased propensity to form VBNR subpopulations may impact TB treatment outcome.
目前的结核病（TB）治疗方法通常对药物敏感的结核分枝杆菌有效，但由于获得性耐药或表型耐药，治疗可能会失败。结核分枝杆菌持续存在者，即具有存活但非复制能力（VBNR）的抗生素耐受细菌的亚群，被认为是导致结核病治疗结果不佳的原因之一。在这项探索性研究中，我们研究了来自结核病患者的未经治疗的药物敏感临床分离株，这些患者随后的治疗结果并不成功。这些分离株与治愈患者的分离株进行了比较，以评估它们形成 VBNR 亚群的能力。与治愈病例的分离株（0-1.63%）相比，来自治疗结果不佳患者的临床分离株在感染 THP-1 巨噬细胞后形成更大比例的 VBNR 结核分枝杆菌（2.67-13.71%）。所有分离株基于表型和基因型分析均为药物敏感。全基因组测序确定了 23 个治疗失败临床分离株共有的非同义基因组变异，这些变异不存在于治愈病例的分离株中。这项探索性研究强调了未经治疗的临床分离株形成包含 VBNR 结核分枝杆菌的异质群体的能力。我们还证明了来自治疗结果不佳患者的临床分离株形成更高比例的 VBNR 结核分枝杆菌。这项探索性研究的结果表明，形成 VBNR 亚群的倾向增加可能会影响结核病的治疗结果。
