Meng Fanrong, Chen Yuanjin, Wei Zeyou, Liu Zhihui, Lai Xiaomin, Lei Jie, Wu Ling, Deng Li, Wang Qi, Yang Yu, Li Hua, Xie Bei, Gong Lan, Niu Qun, Gao Junwen, Wang Nan, Hu Jinxing
State Key Laboratory of Respiratory Disease, Guangzhou Key Laboratory of Tuberculosis Research, Institute of Pulmonary Diseases, Guangzhou Chest Hospital, Institute of Tuberculosis, Guangzhou Medical University, Guangzhou, People's Republic of China.
Sun Yat-Sen University, School of Public Health, Shen Zhen, People's Republic of China.
Ann Clin Microbiol Antimicrob. 2025 Aug 31;24(1):48. doi: 10.1186/s12941-025-00816-5.
While several recent studies have documented the importance of efflux pumps as mediators of rifampin (RIF) resistance, it remains uncertain which efflux pumps play major roles in rifampin-resistant Mycobacterium tuberculosis strains harboring rpoB gene mutations.
In this study, minimum inhibitory concentration (MIC) values for RIF were calculated and the expression of 13 efflux pump genes was evaluated across 35 clinical rifampicin-resistant M. tuberculosis isolates carrying the rpoB mutation before and after efflux pump inhibitor treatment.
Rv0677c and Rv0191 were identified as the efflux pump genes that were most frequently overexpressed, and treatment with the inhibitor verapamil was sufficient to synergistically enhance the antibacterial effects of RIF and downregulate efflux pump gene expression. Greater numbers of overexpressed efflux pump genes were associated with a more significant decrease in the MIC value for RIF following verapamil treatment. Levels of RIF resistance for clinical isolates with the rpoB codon 445 mutation were also found to be significantly less susceptible to the effects of verapamil as compared to the resistance of strains with the codon 450 and 170 mutations.
These results suggest that levels of RIF resistance in clinical RIF-resistant M. tuberculosis isolates are ultimately determined by a combination of efflux pump activity and rpoB gene mutations.
虽然最近的几项研究已证明外排泵作为利福平（RIF）耐药性介导因子的重要性，但仍不确定哪些外排泵在携带rpoB基因突变的耐利福平结核分枝杆菌菌株中起主要作用。
在本研究中，计算了利福平的最低抑菌浓度（MIC）值，并评估了35株携带rpoB突变的临床耐利福平结核分枝杆菌分离株在接受外排泵抑制剂治疗前后13种外排泵基因的表达情况。
Rv0677c和Rv0191被确定为最常过度表达的外排泵基因，用抑制剂维拉帕米治疗足以协同增强利福平的抗菌作用并下调外排泵基因表达。过度表达的外排泵基因数量越多，维拉帕米治疗后利福平的MIC值下降越显著。还发现，与密码子450和170突变的菌株相比，具有rpoB密码子445突变的临床分离株对维拉帕米的耐药水平对其作用的敏感性明显较低。
这些结果表明，临床耐利福平结核分枝杆菌分离株的利福平耐药水平最终由外排泵活性和rpoB基因突变共同决定。
