Large-scale genomic analysis of Mycobacterium tuberculosis reveals extent of target and compensatory mutations linked to multi-drug resistant tuberculosis.
Large-scale genomic analysis of Mycobacterium tuberculosis reveals extent of target and compensatory mutations linked to multi-drug resistant tuberculosis.
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DOI：
10.1038/s41598-023-27516-4
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发表时间：
2023-01-12
影响因子：
4.6
通讯作者：
中科院分区：
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结核分枝杆菌 (Mtb) 对异烟肼 (INH) 和利福平 (RIF) 一线药物的耐药性（统称为多重耐药性）威胁着结核病的控制。 katG（INH）和 rpoB（RIF）基因的抗性突变通常会带来适应性成本。为了克服这些成本，在 rpoC/rpoA (RIF) 和 ahpC (INH) 基因座中出现了 Mtb 补偿性突变。通过利用已知补偿性突变的存在，我们旨在检测 INH 和 RIF 靶基因中发生的新型耐药突变。在具有全基因组测序 (WGS) 数据的 ~ 32 k Mtb 分离株中，有 6262 株 (35.7%) 具有 INH，5435 株 (30.7%) 具有 RIF 表型抗性。 katG 和 rpoB 的已知突变解释了 99% 的耐药性。然而，188 个 (0.6%) 分离株具有 ahpC 补偿突变，而 katG 中没有已知的抗性突变，因此在 katG 中鉴定出 31 个假定的抗性突变，每个突变都在至少 3 个分离株中观察到。这些推定的 katG 突变可以与其他 INH 变体（例如 katG-Ser315Thr、fabG1 突变）同时发生。对于 RIF，没有分离出带有 rpoC/rpoA 补偿突变和未知耐药突变的菌株。总体而言，利用全基因组测序数据，我们确定了 INH 的假定耐药标记，可用于基因型耐药分析。建立完整的结核分枝杆菌耐药突变库将有助于结核病的临床管理。
Resistance to isoniazid (INH) and rifampicin (RIF) first-line drugs in Mycobacterium tuberculosis (Mtb), together called multi-drug resistance, threatens tuberculosis control. Resistance mutations in katG (for INH) and rpoB (RIF) genes often come with fitness costs. To overcome these costs, Mtb compensatory mutations have arisen in rpoC/rpoA (RIF) and ahpC (INH) loci. By leveraging the presence of known compensatory mutations, we aimed to detect novel resistance mutations occurring in INH and RIF target genes. Across ~ 32 k Mtb isolates with whole genome sequencing (WGS) data, there were 6262 (35.7%) with INH and 5435 (30.7%) with RIF phenotypic resistance. Known mutations in katG and rpoB explained ~ 99% of resistance. However, 188 (0.6%) isolates had ahpC compensatory mutations with no known resistance mutations in katG, leading to the identification of 31 putative resistance mutations in katG, each observed in at least 3 isolates. These putative katG mutations can co-occur with other INH variants (e.g., katG-Ser315Thr, fabG1 mutations). For RIF, there were no isolates with rpoC/rpoA compensatory mutations and unknown resistance mutations. Overall, using WGS data we identified putative resistance markers for INH that could be used for genotypic drug-resistance profiling. Establishing the complete repertoire of Mtb resistance mutations will assist the clinical management of tuberculosis.
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DOI：
10.1093/bioinformatics/btq033
发表时间：
2010-03-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
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作者：
Quinlan AR;Hall IM
通讯作者：
Hall IM
影响因子：
4.3
作者：
Libiseller-Egger J;Phelan J;Campino S;Mohareb F;Clark TG
通讯作者：
Clark TG
影响因子：
30.8
作者：
Comas, Inaki;Borrell, Sonia;Roetzer, Andreas;Rose, Graham;Malla, Bijaya;Kato-Maeda, Midori;Galagan, James;Niemann, Stefan;Gagneux, Sebastien
通讯作者：
Gagneux, Sebastien
影响因子：
4.9
作者：
Hazbon, Manzour Hernando;Brimacombe, Michael;Alland, David
通讯作者：
Alland, David
使用下一代 DNA 测序数据进行变异发现和基因分型的框架。
影响因子：
30.8
作者：
通讯作者：
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