Perchlozone ([PCZ] 4-thioureido-iminomethylpyridinium perchlorate) is a new thiosemicarbazone approved for the treatment of multidrug-resistant tuberculosis (MDR-TB) in Russia and some other countries. The ethA and hadABC mutations may confer PCZ resistance. At the same time, ethA mutations are known to mediate resistance to ethionamide (ETH) and prothionamide (PTH). We aimed to study the genetic variation underlying Mycobacterium tuberculosis resistance to PCZ through whole genome sequencing (WGS) of consecutive isolates recovered during long-term treatment. This prospective study included patients admitted in 2018–2019 to the regional tuberculosis dispensary, Kaliningrad, Russia, whose treatment regimen included PCZ. Multiple M. tuberculosis isolates were recovered during PCZ treatment, and the bacterial DNA was subjected to WGS followed by bioinformatics analysis. We identified mutations in the genes putatively associated with PCZ resistance, ethA, and hadA. The most frequent one was a frameshift ethA 106 GA > G (seven of nine patients) and most of the other mutations were also likely present before PCZ treatment. In one patient, a frameshift mutation ethA 702 CT > C emerged after six months of PCZ treatment. A frequent presence of cross-resistance mutations to PCZ and ETH/PTH should be taken into consideration when PCZ is included in the treatment regimen of MDR-TB patients.

中文翻译：

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遗传变异与结核分枝杆菌对Perchlozone（一种新的硫脲类抗生素）的抗性相关：来自全基因组测序的线索及其对耐多药结核病的治疗意义

Perchlozone（[PCZ] 4-硫脲基-亚氨基甲基吡啶高氯酸盐）是一种新的硫代氨基脲，在俄罗斯和其他一些国家/地区被批准用于治疗耐多药结核病（MDR-TB）。该ETHA和hadABC突变可能赋予PCZ阻力。同时，已知ethA突变可介导对乙硫酰胺（ETH）和乙硫酰胺（PTH）的抗性。我们旨在通过长期治疗中回收的连续分离株的全基因组测序（WGS），研究结核分枝杆菌对PCZ耐药的潜在遗传变异。这项前瞻性研究纳入了2018-2019年收治于俄罗斯加里宁格勒地区结核病诊治所的患者，其治疗方案包括PCZ。多在PCZ处理期间回收了结核分枝杆菌分离株，并对细菌DNA进行了WGS处理，然后进行了生物信息学分析。我们确定了与PCZ抗性，ethA和hadA相关的基因突变。频率最高的是ethA 106 GA> G移码（9位患者中有7位），其他大多数突变也可能在PCZ治疗之前出现。一名患者在PCZ治疗六个月后出现了移码突变ethA 702 CT>C。当MDR-TB患者的治疗方案中包括PCZ时，应考虑到PCZ和ETH / PTH的交叉耐药性突变的频繁出现。