通过全基因组分析鉴定结核分枝杆菌分离株耐药机制中的新型单核苷酸变异。
Identification of novel single nucleotide variants in the drug resistance mechanism of Mycobacterium tuberculosis isolates by whole-genome analysis.
机构信息
School of Artificial Intelligence, Hangzhou Dianzi University, Hangzhou, 310018, China.
Agricultural Bioinformatics Key Laboratory of Hubei Province and 3D Genomics Research Centre, College of Informatics, Huazhong Agricultural University, Wuhan, 430070, China.
出版信息
BMC Genomics. 2024 May 14;25(1):478. doi: 10.1186/s12864-024-10390-3.
BACKGROUND
Tuberculosis (TB) represents a major global health challenge. Drug resistance in Mycobacterium tuberculosis (MTB) poses a substantial obstacle to effective TB treatment. Identifying genomic mutations in MTB isolates holds promise for unraveling the underlying mechanisms of drug resistance in this bacterium.
METHODS
In this study, we investigated the roles of single nucleotide variants (SNVs) in MTB isolates resistant to four antibiotics (moxifloxacin, ofloxacin, amikacin, and capreomycin) through whole-genome analysis. We identified the drug-resistance-associated SNVs by comparing the genomes of MTB isolates with reference genomes using the MuMmer4 tool.
RESULTS
We observed a strikingly high proportion (94.2%) of MTB isolates resistant to ofloxacin, underscoring the current prevalence of drug resistance in MTB. An average of 3529 SNVs were detected in a single ofloxacin-resistant isolate, indicating a mutation rate of approximately 0.08% under the selective pressure of ofloxacin exposure. We identified a set of 60 SNVs associated with extensively drug-resistant tuberculosis (XDR-TB), among which 42 SNVs were non-synonymous mutations located in the coding regions of nine key genes (ctpI, desA3, mce1R, moeB1, ndhA, PE_PGRS4, PPE18, rpsA, secF). Protein structure modeling revealed that SNVs of three genes (PE_PGRS4, desA3, secF) are close to the critical catalytic active sites in the three-dimensional structure of the coding proteins.
CONCLUSION
This comprehensive study elucidates novel resistance mechanisms in MTB against antibiotics, paving the way for future design and development of anti-tuberculosis drugs.
背景
结核病（TB）是一个重大的全球健康挑战。结核分枝杆菌（MTB）的耐药性对有效治疗 TB 构成了重大障碍。鉴定 MTB 分离株中的基因组突变有望揭示该细菌耐药性的潜在机制。
方法
在这项研究中，我们通过全基因组分析研究了 MTB 分离株对四种抗生素（莫西沙星、氧氟沙星、阿米卡星和卷曲霉素）耐药的单核苷酸变异（SNVs）的作用。我们通过使用 MuMmer4 工具将 MTB 分离株的基因组与参考基因组进行比较，确定了与耐药相关的 SNVs。
结果
我们观察到耐氧氟沙星的 MTB 分离株比例非常高（94.2%），突显了 MTB 目前耐药的普遍性。在单个耐氧氟沙星的分离株中检测到平均 3529 个 SNVs，表明在氧氟沙星暴露的选择压力下，突变率约为 0.08%。我们鉴定了一组 60 个与广泛耐药结核病（XDR-TB）相关的 SNVs，其中 42 个 SNVs是非同义突变，位于九个关键基因（ctpI、desA3、mce1R、moeB1、ndhA、PE_PGRS4、PPE18、rpsA、secF）的编码区。蛋白质结构建模表明，三个基因（PE_PGRS4、desA3、secF）的 SNVs 接近编码蛋白三维结构中关键催化活性位点。
结论
这项全面的研究阐明了 MTB 对抗生素的新耐药机制，为未来抗结核药物的设计和开发铺平了道路。
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