Targeted sequencing of drug resistance genes Mycobacterium tuberculosis

INTRODUCTION. Drug-resistant forms of tuberculosis and their prevalence are an urgent problem of modern medicine. Genetic mechanisms of drug resistance are the key to understanding the possibilities of diagnostic methods for therapy-resistant tuberculosis. Currently, both phenotypic signs of pathogen resistance to TB drugs and genetic markers of resistance are being identified. A wide range of thematic publications and studies on gene mutations is associated with resistance to TB drugs. OBJECTIVE. Analyze the most effective molecular biological technologies and methods allowing to determine resistance of the tuberculosis pathogen to drugs recommended by the World Health Organization (WHO) in treatment regimens. To present the highest incidence of individual mutations associated with antibiotic resistance genes, which form a significant level of resistance to antituberculosis drugs. Consider the spectrum of mutations of drug resistance genes that provide the greatest contribution to its formation.

MATERIALS AND METHODS. Materials of Russian and foreign authors, WHO recommendations related to the prevalence and assessment of the significance of mutations of individual antibiotic resistance genes in different countries and regions were used. Periodical literature sources from international and Russian free databases were analyzed: PubMed, WHO website (https://www.who.int), international tuberculosis database - Tuberculosis Drug Resistance Mutation Database (TBDReaMDB). (http://www.tbdreamdb.com), MDPI, eLIBRARY, CyberLeninka, and a sample of articles by keywords for 20 years (from 2004 to 2024).

RESULTS. The most effective molecular biological technologies that enable the detection of mutations in drug resistance genes are presented. Targeted sequencing allows the targeted selection of primers to fragments of genes associated with drug resistance to obtain the results necessary to assess the level of resistance of mycobacteria to the main drugs included in the treatment regimen. The most frequent localizations of mutations in Mycobacterium tuberculosis genes associated with significant levels of drug resistance have been systematized. DISCUSSION. The prevalence of drug-resistant strains varies across countries and regions and can only be compared using a reliable and verifiable genetic method. Targeted sequencing is a method for effective surveillance of drug-resistant TB, and phenotypic testing in the Bactec MGIT system is used to validate this information. Results of the prevalence of single nucleotide polymorphisms obtained by sequencing methods should complement and clarify the data detected by PCR methods.

CONCLUSION. Targeted Sanger sequencing of drug resistance genes occupies a worthy place among other molecular genetic methods of tuberculosis research. Targeted sequencing has a special role in the analysis of genes associated with drug resistance to long-standing first-line drugs with atypical localization of mutations; it is also the only method for the study of genes associated with resistance to new and emerging drugs. Adequate selection of primer sets for the regions of drug resistance genes encoding polypeptide chain positions in M. tuberculosis enzyme complexes that are critical for the correct formation of the globular structure plays a key role in the efficiency of Sanger sequencing.

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