Genetic Profile of Linezolid-Resistant M. tuberculosis Clinical Strains from Moscow

Abstract

Background: Linezolid, bedaquiline, and newer fluoroquinolones are currently placed as priority Group A drugs for the treatment of drug-resistant tuberculosis. The number of reported linezolid-resistant clinical strains is still low, and the correlation of molecular determinants with phenotype is not perfect. Methods: We determined the linezolid MICs for clinical isolates from the Moscow region and identified mutations in rplC and rrl genes. Results: All 16 linezolid-resistant isolates had previously reported mutations in the rplC or rrl loci, and 13 of them bore a RplC C154R substitution. Detection of this substitution in a heteroresistant state was not successful, probably, due to the more stable DNA secondary structure of the mutated fragment, which precludes its amplification in mixes with the wild-type DNA. Strains with an rplC mutation had higher linezolid MIC compared to isolates with rrl mutations. Conclusions: Linezolid resistance mostly emerged during treatment with the latest regimen. Three primary cases with linezolid resistance question the possible transmission of totally drug-resistant tuberculosis in the Moscow region, which demands further investigation.

Navigating the Challenge of Tuberculosis Drug Resistance: Unveiling Intrinsic and Acquired Pathways to Overcome the Threat

“…Ribosomal protein L3 (rplC) gene mutations like C154R are prevalent. Rare rrl and rplD gene mutations have been found [128]. Linezolid is aggressively removed from bacterial cells by efflux pumps, making XDR-TB isolates resistant to it.…”

Mutations and insights into the molecular mechanisms of resistance of Mycobacterium tuberculosis to first-line

“…The resistance mechanism for LNZ involves, primarily, mutations to ribosomal protein L3 and subunit 23S, encoded by genes rplC and rrl, respectively. The mutation C154R in RplC is one of the most prevalent ones (Ushtanit et al, 2021). Nevertheless, other mutations reported to LZD were summarized by Kadura et al (2020) and Khosravi et al (2021).…”

Mechanisms of Linezolid Resistance in Mycobacteria

“…As such, mutations to the 23S rRNA are also quite frequently observed in linezolid-resistant mycobacteria [ 61 ]. Mutations in the rrl gene, which encodes the 23S rRNA, have been observed in many clinical isolates, particularly g2814t, which has been reported in many locations as far apart as India, South Africa, and Russia [ 45 , 46 , 47 , 52 ].…”

“…In a study from India, linezolid-resistant MTB was found in about 6.7% (23/343) of patients diagnosed with MDR-TB [ 46 ]. Researchers from Moscow reported the emergence of linezolid-resistant strains from TB patients undergoing treatment with Group A drugs that included linezolid [ 47 ]. In their cohort of XDR-TB patients, 6.21% (20/322) were found to have linezolid-resistant MTB.…”