Ushtanit Anastasia, Mikhailova Yulia, Krylova Ludmila, Grigorash Dmitry, Makarova Marina, Safonova Svetlana, Zimenkov Danila
Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia.
The Moscow Research and Clinical Center for Tuberculosis Control, Moscow Government Health Department, 107014 Moscow, Russia.
Antibiotics (Basel). 2023 Mar 15;12(3):590. doi: 10.3390/antibiotics12030590.
The emergence of drug-resistant tuberculosis forced the development of new drugs and the screening of more effective or less toxic analogues. Mycolic acid biosynthesis is targeted by several antituberculosis drugs, isoniazid being one of the most important in tuberculosis therapy. Recently, perchlozone, acting on another step in the FAS-II cycle, was officially approved for tuberculosis treatment in the Russian Federation and was included in the Russian national clinical guidelines. Using the serial dilution method on 7H10 agar plates for perchlozone and a Sensititre MYCOTB microdilution plate, we analyzed the phenotypic properties of primary clinical isolates of and analyzed the molecular determinants of resistance to isoniazid, ethionamide, and perchlozone. We found a wide variation in the MIC of perchlozone from 2 to 64 mg/L, correlating with the overall resistance profile: the MIC was higher for MDR and pre-XDR isolates. The cross-resistance between ethionamide and perchlozone was driven by mutations in the gene encoding monooxygenase responsible for the activation of both drugs. The presumably susceptible to perchlozone and wild-type strains had MICs ranging from 2 to 4 mg/L, and the breakpoint was estimated to be 4 or 8 mg/L. In conclusion, susceptibility to perchlozone is retained for a part of the MDR strains, as is susceptibility to ethionamide, providing the possibility of therapy for such cases based on phenotypic or molecular analysis.
耐多药结核病的出现促使了新药的研发以及更有效或毒性更低的类似物的筛选。分枝菌酸生物合成是多种抗结核药物的作用靶点，异烟肼是结核病治疗中最重要的药物之一。最近，作用于脂肪酸合成Ⅱ型循环另一步骤的全氯酮在俄罗斯联邦正式获批用于结核病治疗，并被纳入俄罗斯国家临床指南。我们使用全氯酮在7H10琼脂平板上的系列稀释法以及Sensititre MYCOTB微量稀释平板，分析了结核分枝杆菌临床分离株的表型特性，并分析了对异烟肼、乙硫异烟胺和全氯酮耐药的分子决定因素。我们发现全氯酮的最低抑菌浓度（MIC）在2至64mg/L之间有很大差异，这与总体耐药情况相关：耐多药和广泛耐药前分离株的MIC更高。乙硫异烟胺和全氯酮之间的交叉耐药是由负责两种药物激活的单加氧酶编码基因的突变驱动的。推测对全氯酮敏感的野生型菌株的MIC范围为2至4mg/L，断点估计为4或8mg/L。总之，一部分耐多药菌株对全氯酮仍保持敏感性，对乙硫异烟胺也是如此，这为基于表型或分子分析对这类病例进行治疗提供了可能性。
