Rv0678、Rv2535c 和 Rv1979c 基因突变导致临床结核分枝杆菌对贝达喹啉产生耐药性。

Khaoula Balgouthi, Manaf AlMatar, Hamza Saghrouchni, Osman Albarri, Işıl Var
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引用次数: 0

摘要

导言:结核分枝杆菌(MTB)的 Rv0678、epQ 和 Rv1979c 基因突变与贝达喹啉(BDQ)对抗结核药物的敏感性降低有关。正在接受治疗的 MTB 菌株中的致耐药性突变可能会对旨在缩短治疗时间的基于 BDQ 的新型药物治疗方案产生影响。因此,我们研究了土耳其肺结核患者临床分离的 MTB 菌株对 BDQ 产生耐药性的基因基础。此外,我们还将与外排泵相关的基因突变作为一种后备耐药机制进行了研究:方法:我们采用便利抽样法仔细检查了来自结核病患者的 100 例 MTB 临床分离株。这些分离株中有 80 株 MDR MTB 和 20 株泛药敏 MTB。我们对所有菌株进行了测序,并通过基因组分析发现了 BDQ 耐药性相关基因的突变,包括 Rv0678 和 pepQ(Rv2535c)(对应于一种假定的 Xaa-Pro 氨基肽酶)以及 Rv1979c。在 PepQ(Rv2535c)突变的 74 个分离株中,有 4 个分离株(2.96%)表现出对 MGIT-BDQ 的敏感性:结果:在包括 Rv1979c 在内的 91 个携带突变的分离株中,有 21 个(19.11%)对 MGIT-BDQ 敏感。然而,在 39 个携带 Rv0678 突变的分离株中,有 4 个(2.96%)对 MGIT-BDQ 敏感。研究发现,Rv0678、pepQ 和 Rv1979c 中的抗性相关变异(RAVs)往往与 BDQ 抗性有关:结论:为了将外排泵基因变异纳入耐药 MTB 的基因组诊断中,需要进一步证明它们与耐药性的关系。
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Mutations in Rv0678, Rv2535c, and Rv1979c Confer Resistance to Bedaquiline in Clinical Isolates of Mycobacterium Tuberculosis.

Introduction: Reduced bedaquiline (BDQ) sensitivity to antimycobacterial drugs has been linked to mutations in the Rv0678, pepQ, and Rv1979c genes of Mycobacterium tuberculosis (MTB). Resistance-causing mutations in MTB strains under treatment may have an impact on novel BDQ-based medication regimens intended to reduce treatment time. Due to this, we investigated the genetic basis of BDQ resistance in Turkish TB patients with MTB clinical isolates. Furthermore, mutations in the genes linked to efflux pumps were examined as a backup resistance mechanism.

Methods: We scrutinized 100 MTB clinical isolates from TB patients using convenience sampling. Eighty MDR and twenty pan-drug susceptible MTB strains were among these isolates. Sequencing was performed on all strains, and genomic analyses were performed to find mutations in BDQ resistance-associated genes, including Rv0678 and pepQ(Rv2535c), which correspond to a putative Xaa-Pro aminopeptidase, and Rv1979c. Of the 74 isolates with PepQ (Rv2535c) mutations, four isolates (2.96%) exhibited MGIT-BDQ susceptibility.

Results: Twenty-one (19.11%) of the ninety-one isolates carrying mutations, including Rv1979c, were MGIT-BDQ-sensitive. Nonetheless, out of the 39 isolates with Rv0678 mutations, four (2.96%) were sensitive to MGIT-BDQ. It was found that resistance-associated variants (RAVs) in Rv0678, pepQ, and Rv1979c are often linked to BDQ resistance.

Conclusion: In order to include variations in efflux pump genes in genome-based diagnostics for drug-resistant MTB, further evidence about their involvement in resistance is needed.

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