Department of Integrated Biological Science, Pusan National University, Busan, 46241, Korea.
Division of Bacterial Disease Research, Center for Infectious Disease Research, National Institute of Infectious Diseases, National Institute of Health, Korea Disease Control and Prevention Agency, Osong, 28159, Korea.
J Microbiol. 2022 Sep;60(9):935-947. doi: 10.1007/s12275-022-2202-0. Epub 2022 Aug 1.
Using a mutant of Mycobacterium smegmatis lacking the major aa cytochrome c oxidase of the electron transport chain (Δaa), we demonstrated that inhibition of the respiratory electron transport chain led to an increase in antibiotic resistance of M. smegmatis to isoniazid, rifampicin, ethambutol, and tetracycline. The alternative sigma factors SigB and SigE were shown to be involved in an increase in rifampicin resistance of M. smegmatis induced under respiration-inhibitory conditions. As in Mycobacterium tuberculosis, SigE and SigB form a hierarchical regulatory pathway in M. smegmatis through SigE-dependent transcription of sigB. Expression of sigB and sigE was demonstrated to increase in the Δaa mutant, leading to upregulation of the SigB-dependent genes in the mutant. The pho U2 (MSMEG_1605) gene implicated in a phosphate-signaling pathway and the MSMEG_1097 gene encoding a putative glycosyltransferase were identified to be involved in the SigB-dependent enhancement of rifampicin resistance observed for the Δaa mutant of M. smegmatis. The significance of this study is that the direct link between the functionality of the respiratory electron transport chain and antibiotic resistance in mycobacteria was demonstrated for the first time using an electron transport chain mutant rather than inhibitors of electron transport chain.
利用一株缺乏电子传递链主要 aa 细胞色素 c 氧化酶的耻垢分枝杆菌突变株（Δaa），我们证明了抑制呼吸电子传递链会导致耻垢分枝杆菌对抗结核药物异烟肼、利福平、乙胺丁醇和四环素的耐药性增加。研究表明，在呼吸抑制条件下，替代 sigma 因子 SigB 和 SigE 参与了耻垢分枝杆菌对利福平耐药性的增加。与结核分枝杆菌一样，SigE 和 SigB 通过 SigE 依赖的 sigB 转录在耻垢分枝杆菌中形成一个分层的调控途径。实验证明，在Δaa 突变株中 sigB 和 sigE 的表达增加，导致突变株中 SigB 依赖基因的上调。参与磷酸盐信号通路的 pho U2（MSMEG_1605）基因和编码假定糖基转移酶的 MSMEG_1097 基因被确定为与 SigB 依赖的耻垢分枝杆菌 Δaa 突变株中观察到的利福平耐药性增强有关。本研究的意义在于，首次利用电子传递链突变体而非电子传递链抑制剂，证明了分枝杆菌呼吸电子传递链的功能与抗生素耐药性之间的直接联系。
