Zein-Eddine R, Le Meur A, Skouloubris S, Jelsbak L, Refrégier G, Myllykallio H
Laboratoire d'Optique et Biosciences (LOB), Ecole Polytechnique, Inserm U1182, CNRS UMR7645, Institut Polytechnique de Paris, Palaiseau, France.
Laboratoire d'Ecologie Systématique et Evolution, CNRS UMR8079, AgroParisTech, Gif-Sur-Yvette, France.
NPJ Antimicrob Resist. 2025 Apr 29;3(1):35. doi: 10.1038/s44259-025-00107-1.
Antimicrobial combination therapy is widely used to combat Mycobacterium tuberculosis (Mtb), yet resistance rates continue to rise. Mutator strains, with defects in DNA repair genes, drive resistance in other bacterial infections, but their role in Mtb remains unclear. Here, we study the contribution of single nucleotide polymorphisms (SNPs) in DNA Repair, Replication, and Recombination (3 R) genes to Mtb resistance. Through large-scale bioinformatics analysis of 53,589 whole-genomes, we identified 18 novel SNPs in lineages 2 and 4 linked to genotypic drug resistance in 3 R genes, covering 12.5% of clinical isolates with available genome sequences. Notably, a number of the detected SNPs were positively selected during Mtb evolution. Experimental tests showed that mutM, fpgg2, xthA, and nucS mutants had increased the mutation frequency compared to the wild type. Our findings highlight the role of 3 R gene mutations in resistance, emphasizing the need for surveillance to improve early detection and control strategies.
抗菌联合疗法被广泛用于对抗结核分枝杆菌（Mtb），但其耐药率仍在不断上升。具有DNA修复基因缺陷的突变菌株在其他细菌感染中导致耐药性，但它们在结核分枝杆菌中的作用仍不清楚。在这里，我们研究DNA修复、复制和重组（3R）基因中的单核苷酸多态性（SNP）对结核分枝杆菌耐药性的贡献。通过对53589个全基因组的大规模生物信息学分析，我们在2型和4型谱系中鉴定出18个与3R基因中的基因型耐药性相关的新SNP，覆盖了12.5%具有可用基因组序列的临床分离株。值得注意的是，在结核分枝杆菌进化过程中，许多检测到的SNP被正向选择。实验测试表明，与野生型相比，mutM、fpgg2、xthA和nucS突变体的突变频率增加。我们的研究结果突出了3R基因突变在耐药性中的作用，强调了进行监测以改进早期检测和控制策略的必要性。
