Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, China.
Tuberculosis (Edinb). 2024 Sep;148:102551. doi: 10.1016/j.tube.2024.102551. Epub 2024 Jul 26.
As one of the factors affecting the treatment outcomes, drug tolerance in mycobacteriosis has not been paid due attention. Genome-wide association studies on 607 Mycobacterium tuberculosis clinical isolates with phenotypic drug susceptibility test data revealed that a K114N mutation on the rv2820c gene was highly enriched in capreomycin-resistant isolates (32/213, 15.02%). However, the mutation was also observed in capreomycin-sensitive isolates (10/394, 2.53%). In most cases (31/42, 73.81%), the rv2820c K114N mutation occurred in isolates with the known capreomycin resistance conferring mutation rrs A1401G. In contrast, the general frequency of the rv2820c K114N mutation was low in 7061 genomes downloaded from the National Center for Biotechnology Information database. To determine the impact of this mutation on the antimycobacterial activity of capreomycin, the intact rv2820c gene and the rv2820c K114N mutant were over-expressed in Mycobacterium smegmatis (Ms), and the results of susceptibility tests showed that the rv2820c K114N mutation did not affect the minimum inhibition concentration (MIC) of capreomycin. Subsequently, the data of time-kill assays showed that, it took only 2 h of capreomycin treatment (40 μg/ml, 5 × MIC) to kill 99.9% bacterial cells of Ms MC155 pMV261::rv2820c, while it took 6 h to achieve that for Ms MC155 pMV261::rv2820c. Taken together, these data suggested that the rv2820c K114N mutation is related with capreomycin tolerance, which merits further investigation.
作为影响治疗结果的因素之一，分枝杆菌病中的药物耐受性尚未得到应有的重视。对 607 株具有表型药敏试验数据的结核分枝杆菌临床分离株进行全基因组关联研究显示，rv2820c 基因上的 K114N 突变在卷曲霉素耐药分离株中高度富集（32/213，15.02%）。然而，该突变也存在于卷曲霉素敏感分离株中（10/394，2.53%）。在大多数情况下（31/42，73.81%），rv2820c K114N 突变发生在已知具有卷曲霉素耐药相关突变 rrs A1401G 的分离株中。相比之下，rv2820c K114N 突变的总体频率在从国家生物技术信息中心数据库下载的 7061 个基因组中较低。为了确定该突变对卷曲霉素抗分枝杆菌活性的影响，在耻垢分枝杆菌（Ms）中过表达完整的 rv2820c 基因和 rv2820c K114N 突变体，药敏试验结果表明 rv2820c K114N 突变不影响卷曲霉素的最低抑菌浓度（MIC）。随后，时间杀伤试验数据显示，仅用卷曲霉素处理 2 小时（40μg/ml，5×MIC）即可杀死 Ms MC155 pMV261::rv2820c 的 99.9%细菌细胞，而用 Ms MC155 pMV261::rv2820c 则需要 6 小时。综上所述，这些数据表明 rv2820c K114N 突变与卷曲霉素耐药性有关，值得进一步研究。
