Efflux pump gene single-nucleotide variants associated with resistance in Mycobacterium tuberculosis isolates with discrepant drug genotypes

IF 3.7 3区 医学 Q2 INFECTIOUS DISEASES Journal of global antimicrobial resistance Pub Date : 2024-05-22 DOI:10.1016/j.jgar.2024.05.006
Zahra Hasan , Safina Abdul Razzak , Akbar Kanji, Sadia Shakoor, Rumina Hasan
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引用次数: 0

Abstract

Introduction

Single-nucleotide variants (SNVs) in Mycobacterium tuberculosis (M. tuberculosis) genomes can predict multidrug resistance (MDR) but not all phenotype-genotype correlations can be explained. We investigated SNVs in efflux pumps (EPs) in the context of M. tuberculosis drug resistance.

Methods

We analysed 2221 M. tuberculosis genomes from 1432 susceptible and 200 MDR, 172 pre-extensively drug resistant (XDR) and 417 XDR isolates. Analysis of 47 EP genes was conducted using MTB-VCF, an in-house bioinformatics pipeline. SNVs were categorized according to their SIFT/Polyphen scores. Resistance genotypes were also called using the TB-Profiler tool.

Results

Genome comparisons between susceptible and drug resistant (DR) isolates identified 418 unique SNVs in EP of which; 53.5% were in MDR, 68.9% in pre-XDR and 61.3% in XDR isolates. Twenty EPs had unique SNVs with a high SIFT/PolyPhen score, comprising 38 unique SNVs. Sixteen SNVs across 12 EP genes were significantly associated with drug resistance and enriched in pre-XDR and XDR strains. These comprised 12 previously reported SNVs (in Rv0191, Rv0507, Rv0676, Rv1217, Rv1218, Rv1273, Rv1458, Rv1819, and Rv2688) and 4 novel SNVs (in Rv1877 and Rv2333). We investigated their presence in genomes of 52 MDR isolates with phenotype-genotype discrepancies to rifampicin (RIF), isoniazid (INH), or fluoroquinolones. SNVs associated with RIF and INH (Rv1217_1218, Rv1819, Rv0450, Rv1458, Rv3827, Rv0507, Rv0676, Rv1273, and Rv2333), and with fluoroquinolone (Rv2688) resistance were present in these discrepant strains.

Conclusions

Considering SNVs in EPs as part of M. tuberculosis genome-based resistance interpretation may add value, especially in evaluation of XDR resistance in strains with phenotype-genotype discrepancies.

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与具有不同药物基因型的结核分枝杆菌分离株耐药性相关的外排泵基因单核苷酸变异。
导言:结核分枝杆菌(MTB)基因组中的单核苷酸变异(SNVs)可预测多重耐药性(MDR),但并非所有表型与基因型的相关性都能得到解释。我们研究了MTB耐药性背景下外排泵(EP)中的SNV:我们分析了来自 1432 株易感和 200 株 MDR、172 株预 XDR(广泛耐药)和 417 株 XDR 分离株的 2221 个 MTB 基因组。使用内部生物信息学管道 MTB-VCF 对 47 个 EP 基因进行了分析。SNV 根据其 SIFT/Polyphen 分数进行分类。还使用 TB-Profiler 工具调用了抗药性基因型:结果:易感株和耐药株之间的基因组比较在 EP 中发现了 418 个独特的 SNV,其中 53.5% 在 MDR 中,68.9% 在 pre-XDR 中,61.3% 在 XDR 分离株中。有 20 个 EP 的独特 SNV 具有较高的 SIFT/PolyPhen 分数,包括 38 个独特 SNV。12个EP基因中的16个SNV与耐药性显著相关,并在前XDR和XDR菌株中富集。其中包括 12 个以前报道过的 SNV(在 Rv0191、Rv0507、Rv0676、Rv1217、Rv1218、Rv1273、Rv1458、Rv1819 和 Rv2688 中)和 4 个新的 SNV(在 Rv1877 和 Rv2333 中)。我们研究了 52 个对利福平(RIF)、异烟肼(INH)和氟喹诺酮类药物有表型-基因型差异的 MDR 分离物中的 16 个 SNVs。这些差异菌株中存在与 RIF 和 INH(Rv1217_1218、Rv1819、Rv0450、Rv1458、Rv3827、Rv0507、Rv0676、Rv1273 和 Rv2333)以及氟喹诺酮(Rv2688)耐药性相关的 SNV:将外排泵中的 SNVs 作为基于 MTB 基因组的耐药性解读的一部分可能会增加价值,尤其是在评估表型与基因型不一致的菌株的 XDR 耐药性时。
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来源期刊
Journal of global antimicrobial resistance
Journal of global antimicrobial resistance INFECTIOUS DISEASES-PHARMACOLOGY & PHARMACY
CiteScore
8.70
自引率
2.20%
发文量
285
审稿时长
34 weeks
期刊介绍: The Journal of Global Antimicrobial Resistance (JGAR) is a quarterly online journal run by an international Editorial Board that focuses on the global spread of antibiotic-resistant microbes. JGAR is a dedicated journal for all professionals working in research, health care, the environment and animal infection control, aiming to track the resistance threat worldwide and provides a single voice devoted to antimicrobial resistance (AMR). Featuring peer-reviewed and up to date research articles, reviews, short notes and hot topics JGAR covers the key topics related to antibacterial, antiviral, antifungal and antiparasitic resistance.
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