Irish Mycobacteria Reference Laboratory, St James's Hospital, Dublin, Ireland.
Department of Clinical Microbiology, School of Medicine, Trinity College Dublin, the University of Dublin, St James's Hospital Campus, Dublin, Ireland.
J Antimicrob Chemother. 2023 Nov 6;78(11):2637-2644. doi: 10.1093/jac/dkad252.
WGS has the potential to detect resistance-associated mutations and guide treatment of MDR TB. However, the knowledge base to confidently interpret mutations associated with the new and repurposed drugs is sparse, and phenotypic drug susceptibility testing is required to detect resistance.
We screened 900 Mycobacterium tuberculosis complex genomes from Ireland, a low TB incidence country, for mutations in 13 candidate genes and assessed their association with phenotypic resistance to bedaquiline, clofazimine, linezolid, delamanid and pretomanid.
We identified a large diversity of mutations in the candidate genes of 195 clinical isolates, with very few isolates associated with phenotypic resistance to bedaquiline (n = 4), delamanid (n = 4) and pretomanid (n = 2). We identified bedaquiline resistance among two drug-susceptible TB isolates that harboured mutations in Rv0678. Bedaquiline resistance was also identified in two MDR-TB isolates harbouring Met146Thr in Rv0678, which dated back to 2007, prior to the introduction of bedaquiline. High-level delamanid resistance was observed in two isolates with deletions in ddn, which were also resistant to pretomanid. Delamanid resistance was detected in two further isolates that harboured mutations in fbiA, but did not show cross-resistance to pretomanid. All isolates were susceptible to linezolid and clofazimine, and no mutations found were associated with resistance.
More studies that correlate genotypic and phenotypic drug susceptibility data are needed to increase the knowledge base of mutations associated with resistance, in particular for pretomanid. Overall, this study contributes to the development of future mutation catalogues for M. tuberculosis complex isolates.
WGS 有可能检测到耐药相关突变，并指导 MDR-TB 的治疗。然而，用于准确解释与新的和再利用药物相关的突变的知识库还很缺乏，并且需要进行表型药敏试验来检测耐药性。
我们在爱尔兰筛选了 900 株结核分枝杆菌复合群基因组，这些菌株来自一个低结核病发病率的国家，目的是检测候选基因中的突变与对贝达喹啉、氯法齐明、利奈唑胺、德拉马尼和普托马尼耐药表型的相关性。
在 195 株临床分离株的候选基因中，我们发现了大量的突变，仅有极少数分离株与贝达喹啉（n = 4）、德拉马尼（n = 4）和普托马尼（n = 2）的表型耐药相关。我们在两株药物敏感型结核病分离株中发现了贝达喹啉耐药，这两株分离株都携带有 Rv0678 中的突变。在两株 MDR-TB 分离株中也发现了 Rv0678 中的 Met146Thr 突变导致的贝达喹啉耐药，这两株 MDR-TB 分离株的时间可以追溯到 2007 年，即贝达喹啉上市之前。在两株含有 ddn 缺失的分离株中观察到高水平的德拉马尼耐药，这两株分离株也对普托马尼耐药。在另外两株携带有 fbiA 突变的分离株中检测到了德拉马尼耐药，但它们没有表现出对普托马尼的交叉耐药性。所有分离株均对利奈唑胺和氯法齐明敏感，没有发现与耐药性相关的突变。
需要更多的研究来关联基因型和表型药敏数据，以增加与耐药性相关的突变知识库，特别是针对普托马尼。总的来说，这项研究有助于为结核分枝杆菌复合群分离株的未来突变目录的发展做出贡献。
