Варианты генов Mycobacterium tuberculosis, ассоциированные с лекарственной устойчивостью к фторхинолонам (обзор литературы)

Abstract

Background: The spread of M. tuberculosis drug resistance to fluoroquinolones poses a threat to their long-term clinical efficacy. Understanding the mechanisms of formation of drug resistance to fluoroquinolones, based on information on genes associated with drug resistance of M. tuberculosis, is important for optimizing TB chemotherapy regimens. The aim of the study: To study the available literature data on the most significant variants of M. tuberculosis genes associated with drug resistance to fluoroquinolones. Materials and methods: To achieve this goal, the task was to analyze the sources of domestic and foreign literature on this priority issue over the past 5 years. The databases of scientific electronic libraries PubMed, Elibriary were used. Results: Mycobacterial resistance to fluoroquinolones is associated with mutations in the gyrA and gyrB genes, encoding the GyrA and GyrB subunits of DNA gyrase, the main target of fluoroquinolones. In the fluoroquinolone-binding pocket of the “DNA-gyrase + DNA” catalytic center, the fluoroquinolone molecule is supported by the gyrA and gyrB regions, which determine resistance to fluoroquinolones (QRDR-A and QRDR-B). Modification of any of the constituent fragments of these regions affects the level of resistance to fluoroquinolones. Small quinolone molecules (nalidixic acid) have a high MIC against Mtb and other bacteria, while larger PC molecules (sparfloxacin, sitafloxacin, gatifloxacin, levofloxacin and moxifloxacin) are tightly adjacent to the fluoroquinolone-binding pocket and have a lower MIC. Modification of the DNA structure can change the spatial structure of the pocket itself, which leads to destabilization of the fluoroquinolone inside it. Thus, the presence of heteroresistance of the tuberculosis pathogen to fluoroquinolones indicates the active development of its resistance to this group of drugs in modern conditions. Conclusion: Analysis of modern studies shows the dependence of drug resistance of mycobacteria on fluoroquinolone compounds, while most often resistance to a decrease in the concentration of fluoroquinolones is associated with substitutions in the gyrB gene, as well as mutations in the gyrA gene. It has also been established that in addition to the main studied regions of the gyrA and gyrB genes associated with phenotypic drug resistance to fluoroquinols, there are regions that have not been sufficiently studied so far. These areas cannot be diagnosed in the clinical work of bacteriological laboratories of anti-tuberculosis institutions.