Zhang Lei, Zhang Ye, Li Yuanyuan, Huo Fengmin, Chen Xi, Zhu Hui, Guo Shaochen, Fu Lei, Wang Bin, Lu Yu
Department of Pharmacology, Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute , Beijing, China.
National Clinical Laboratory on Tuberculosis, Beijing Key Laboratory for Drug-Resistant Tuberculosis Research, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Institute , Beijing, China.
Microbiol Spectr. 2023 Aug 24;11(5):e0000223. doi: 10.1128/spectrum.00002-23.
Clofazimine (CFZ) has been repurposed for treating tuberculosis (TB), especially multidrug-resistant tuberculosis (MDR-TB). However, the mechanisms of resistance to clofazimine are poorly understood. We previously reported a mutation located in the intergenic region of that was linked to resistance to CFZ and demonstrated that an knockout resulted in an increased minimum inhibitory concentration (MIC) of CFZ. The current study aims to go back and describe in detail how the mutation was identified and further explore its association with CFZ resistance by testing additional 30 isolates. We investigated MICs of clofazimine against 100 clinical strains isolated from MDR-TB patients by microplate alamarBlue assay. Whole-genome sequencing (WGS) was performed on 11 clofazimine-resistant and 7 clofazimine-susceptible strains, including H37Rv. Among the 11 clofazimine-resistant mutants subjected to WGS, the rate of mutation in the intergenic region of the gene was 55% (6/11) in clofazimine-resistant strains. Among another 30 clofazimine-resistant clinical isolates, 27 had mutations in the intergenic region of the gene. A mutation in the gene associated with clofazimine resistance was identified, which shed light on the mechanisms of action and resistance of clofazimine. IMPORTANCE Tuberculosis (TB) is an infectious disease caused by the bacterium , especially the emergence of multidrug-resistant tuberculosis (MDR-TB) brings great distress to humans. Clofazimine (CFZ) plays an important role in the treatment of MDR-TB. To understand the underlying mechanism of clofazimine resistance better, in this study, we review and detail the findings of the mutation of intergenic region of and find additional evidence that this mutation is related to clofazimine resistance in 30 additional isolates. The significance of our research is to contribute to a comprehensive understanding of clofazimine-resistant mechanisms, which is critical for reducing the emergence of resistance and for anti-TB drug discovery.
氯法齐明（CFZ）已被重新用于治疗结核病（TB），尤其是耐多药结核病（MDR-TB）。然而，对氯法齐明耐药的机制尚不清楚。我们之前报道了位于[基因名称]基因间区域的一个突变，该突变与对CFZ的耐药性有关，并证明敲除[基因名称]会导致CFZ的最低抑菌浓度（MIC）增加。当前的研究旨在回顾并详细描述该突变是如何被鉴定出来的，并通过检测另外30株菌株进一步探索其与CFZ耐药性的关联。我们通过微孔板alamarBlue检测法研究了氯法齐明对从MDR-TB患者中分离出的100株临床菌株的MIC。对11株耐氯法齐明菌株和7株氯法齐明敏感菌株（包括H37Rv）进行了全基因组测序（WGS）。在接受WGS的11株耐氯法齐明突变体中，[基因名称]基因间区域的突变率在耐氯法齐明菌株中为55%（6/11）。在另外30株耐氯法齐明临床分离株中，27株在[基因名称]基因间区域存在突变。鉴定出了一个与氯法齐明耐药相关的[基因名称]基因突变，这为氯法齐明的作用机制和耐药性提供了线索。重要性 结核病（TB）是由[细菌名称]引起的一种传染病，尤其是耐多药结核病（MDR-TB）的出现给人类带来了巨大困扰。氯法齐明（CFZ）在MDR-TB的治疗中发挥着重要作用。为了更好地理解氯法齐明耐药的潜在机制，在本研究中，我们回顾并详细阐述了[基因名称]基因间区域突变的研究结果，并在另外30株分离株中发现了更多该突变与氯法齐明耐药相关的证据。我们研究的意义在于有助于全面了解氯法齐明耐药机制，这对于减少耐药性的出现和抗结核药物研发至关重要。
