Nimmo Camus, Ortiz Arturo Torres, Tan Cedric C S, Pang Juanita, Acman Mislav, Millard James, Padayatchi Nesri, Grant Alison D, O'Donnell Max, Pym Alex, Brynildsrud Ola B, Eldholm Vegard, Grandjean Louis, Didelot Xavier, Balloux François, van Dorp Lucy
UCL Genetics Institute, University College London, Darwin Building, Gower Street, London, UK.
Division of Infection and Immunity, University College London, London, UK.
Genome Med. 2024 Feb 19;16(1):34. doi: 10.1186/s13073-024-01289-5.
Drug resistance in tuberculosis (TB) poses a major ongoing challenge to public health. The recent inclusion of bedaquiline into TB drug regimens has improved treatment outcomes, but this advance is threatened by the emergence of strains of Mycobacterium tuberculosis (Mtb) resistant to bedaquiline. Clinical bedaquiline resistance is most frequently conferred by off-target resistance-associated variants (RAVs) in the mmpR5 gene (Rv0678), the regulator of an efflux pump, which can also confer cross-resistance to clofazimine, another TB drug.
We compiled a dataset of 3682 Mtb genomes, including 180 carrying variants in mmpR5, and its immediate background (i.e. mmpR5 promoter and adjacent mmpL5 gene), that have been associated to borderline (henceforth intermediate) or confirmed resistance to bedaquiline. We characterised the occurrence of all nonsynonymous mutations in mmpR5 in this dataset and estimated, using time-resolved phylogenetic methods, the age of their emergence.
We identified eight cases where RAVs were present in the genomes of strains collected prior to the use of bedaquiline in TB treatment regimes. Phylogenetic reconstruction points to multiple emergence events and circulation of RAVs in mmpR5, some estimated to predate the introduction of bedaquiline. However, epistatic interactions can complicate bedaquiline drug-susceptibility prediction from genetic sequence data. Indeed, in one clade, Ile67fs (a RAV when considered in isolation) was estimated to have emerged prior to the antibiotic era, together with a resistance reverting mmpL5 mutation.
The presence of a pre-existing reservoir of Mtb strains carrying bedaquiline RAVs prior to its clinical use augments the need for rapid drug susceptibility testing and individualised regimen selection to safeguard the use of bedaquiline in TB care and control.
结核病（TB）的耐药性对公共卫生构成了持续的重大挑战。近期将贝达喹啉纳入结核病药物治疗方案改善了治疗效果，但这一进展受到对贝达喹啉耐药的结核分枝杆菌（Mtb）菌株出现的威胁。临床贝达喹啉耐药性最常见的是由mmpR5基因（Rv0678）中的脱靶耐药相关变异（RAV）引起的，mmpR5基因是一种外排泵的调节因子，它也可导致对另一种结核病药物氯法齐明的交叉耐药。
我们汇编了一个包含3682个Mtb基因组的数据集，其中包括180个在mmpR5及其紧邻区域（即mmpR5启动子和相邻的mmpL5基因）携带变异的基因组，这些变异与贝达喹啉的临界（此后称为中度）或确诊耐药相关。我们对该数据集中mmpR5中所有非同义突变的发生情况进行了表征，并使用时间分辨系统发育方法估计了它们出现的时间。
我们在结核病治疗方案中使用贝达喹啉之前收集的菌株基因组中发现了8例存在RAV的情况。系统发育重建表明mmpR5中RAV有多次出现事件和传播，一些估计早于贝达喹啉的引入。然而，上位性相互作用会使从基因序列数据预测贝达喹啉药物敏感性变得复杂。实际上，在一个进化枝中，Ile67fs（单独考虑时为RAV）估计在抗生素时代之前就已出现，同时还有一个使耐药性逆转的mmpL5突变。
在贝达喹啉临床使用之前就存在携带贝达喹啉RAV的Mtb菌株库，这增加了进行快速药物敏感性检测和个体化治疗方案选择的必要性，以保障贝达喹啉在结核病防治中的使用。
