European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, UK; Department of Medicine, University of Cambridge, Cambridge, UK; Centre for Immunology and Infection Control, Queensland University of Technology, Brisbane, QLD, Australia.
European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, UK; Nuffield Department of Medicine, University of Oxford, Oxford, UK.
Lancet Microbe. 2024 Aug;5(8):100847. doi: 10.1016/S2666-5247(24)00053-3. Epub 2024 Jun 5.
The antibiotic bedaquiline is a key component of new WHO regimens for drug-resistant tuberculosis; however, predicting bedaquiline resistance from bacterial genotypes remains challenging. We aimed to understand the genetic mechanisms of bedaquiline resistance by analysing Mycobacterium tuberculosis isolates from South Africa.
For this genomic analysis, we conducted whole-genome sequencing of Mycobacterium tuberculosis samples collected at two referral laboratories in Cape Town and Johannesburg, covering regions of South Africa with a high prevalence of tuberculosis. We used the tool ARIBA to measure the status of predefined genes that are associated with bedaquiline resistance. To produce a broad genetic landscape of M tuberculosis in South Africa, we extended our analysis to include all publicly available isolates from the European Nucleotide Archive, including isolates obtained by the CRyPTIC consortium, for which minimum inhibitory concentrations of bedaquiline were available.
Between Jan 10, 2019, and July, 22, 2020, we sequenced 505 M tuberculosis isolates from 461 patients. Of the 64 isolates with mutations within the mmpR5 regulatory gene, we found 53 (83%) had independent acquisition of 31 different mutations, with a particular enrichment of truncated MmpR5 in bedaquiline-resistant isolates resulting from either frameshift mutations or the introduction of an insertion element. Truncation occurred across three M tuberculosis lineages, and were present in 66% of bedaquiline-resistant isolates. Although the distributions overlapped, the median minimum inhibitory concentration of bedaquiline was 0·25 mg/L (IQR 0·12-0·25) in mmpR5-disrupted isolates, compared with 0·06 mg/L (0·03-0·06) in wild-type M tuberculosis.
Reduction in the susceptibility of M tuberculosis to bedaquiline has evolved repeatedly across the phylogeny. In our data, we see no evidence that this reduction has led to the spread of a successful strain in South Africa. Binary phenotyping based on the bedaquiline breakpoint might be inappropriate to monitor resistance to this drug. We recommend the use of minimum inhibitory concentrations in addition to MmpR5 truncation screening to identify moderate increases in resistance to bedaquiline.
US Centers for Disease Control and Prevention.
抗生素贝达喹啉是世界卫生组织新的耐药结核病治疗方案的关键组成部分；然而，从细菌基因型预测贝达喹啉耐药性仍然具有挑战性。我们旨在通过分析南非的结核分枝杆菌分离株来了解贝达喹啉耐药性的遗传机制。
在这项基因组分析中，我们对开普敦和约翰内斯堡两个转诊实验室采集的结核分枝杆菌样本进行了全基因组测序，这些样本覆盖了南非结核病高发地区。我们使用 ARIBA 工具来测量与贝达喹啉耐药性相关的预定义基因的状态。为了生成南非结核分枝杆菌的广泛遗传景观，我们将分析扩展到包括欧洲核苷酸档案库中所有公开可用的分离株，其中包括 CRyPTIC 联盟获得的分离株，这些分离株的贝达喹啉最低抑菌浓度可用。
在 2019 年 1 月 10 日至 2020 年 7 月 22 日期间，我们对 461 名患者的 505 株结核分枝杆菌进行了测序。在 mmpR5 调节基因内有突变的 64 株分离株中，我们发现 53 株（83%）独立获得了 31 种不同的突变，在贝达喹啉耐药分离株中，MmpR5 的截断特别丰富，这是由于移码突变或插入元件的引入所致。截断发生在三个结核分枝杆菌谱系中，在 66%的贝达喹啉耐药分离株中存在。尽管分布重叠，但 mmpR5 缺失的分离株的贝达喹啉最低抑菌浓度中位数为 0.25mg/L（IQR 0.12-0.25），而野生型结核分枝杆菌的最低抑菌浓度中位数为 0.06mg/L（0.03-0.06）。
结核分枝杆菌对贝达喹啉的敏感性降低已经在系统发育上反复出现。在我们的数据中，我们没有看到这一降低导致一种成功的菌株在南非传播的证据。基于贝达喹啉断点的二元表型可能不适合监测对这种药物的耐药性。我们建议在 MmpR5 截断筛选的基础上使用最低抑菌浓度来识别对贝达喹啉的耐药性适度增加。
美国疾病控制与预防中心。
