Linezolid resistance among multidrug-resistantMycobacterium tuberculosis clinical isolates in Iran

Background and Aim : The management of multidrug-resistant (MDR) and extensively drugresistanttuberculosis (XDR-TB) presents a main challenge and the drug options for treating theseinfections are very limited. Linezolid (LNZ) has recently been approved for the treatment of MDRand XDR-TB. But, there are narrow data on genotypic and phenotypic LNZ resistance in clinicalisolates. So, we aimed to determine the prevalence of LNZ resistance and to identify the mutationsassociated with LNZ resistance among clinical MDR-TB isolates.Methods : Twenty-two MDR-TB clinical isolates were collected from Ahvaz Regional TBLaboratory, Southwest of Iran in ۲۰۲۰. The minimum inhibitory concentration (MIC) values ofLNZ against MDR-TB isolates in a range of concentrations, from ۰.۱۲۵ to ۱۶ mg/L weredetermined by the broth microdilution method. All MDR-TB isolates were sequenced in the rrland rplC genes conferring LNZ resistance. Obtained sequences were aligned together usingClustalW (https://www. genome.jp/tools-bin/clustalw) software to determine the consensussequences. Consensus sequences were subjected to nBLAST analysis(http://blast.ncbi.nlm.nih.gov) and compared with Mycobacterium tuberculosis strain H۳۷Rv.Results : Based on the critical concentration (>۰.۵ mg/L) used for LNZ ۳ isolates (۱۳.۶%) of thetested isolates were resistant that MIC concentrations were ۸ mg/L and >۱۶ mg/L for two and oneisolates, respectively. Eighteen isolates (۸۷.۴%) had MICs ranging from ۰.۱۲۵ to ۰.۵ mg/L andwere susceptible to LNZ. The MIC for the H۳۷Rv strain was ۰.۲۵ mg/L. The genetic analysisillustrated just ۱ of the ۳ LNZ resistant MDR-isolates sequenced carried substitution mutations atnucleotide ۴۲۱ (A/G) and ۴۴۹ (T/A) compared to the reference strain and susceptible isolates,resulting in amino acid exchange from valine to isoleucine at codon ۱۴۱ and isoleucine toasparagine at codon ۱۵۰, respectively. However, no resistance-related mutations were indicated inisolates with MICs below or at the critical concentration. None of the isolates harbored mutationin rrl gene. Furthermore, there was no mutation in rplC and rrl genes among LNZ susceptibleisolates. The obtained nucleotide sequences have been deposited in the GeneBank database underthe MT۴۲۹۷۷۱, MT۴۲۹۷۷۰, MT۴۲۹۷۷۲ (rplC), MT۴۳۱۵۱۵, MT۴۳۱۵۱۶, and MT۴۳۱۵۱۷ (rrl)accession numbers.Conclusion : The results reveal that the prevalence of LNZ-resistant isolates is ۱۳.۶% amongMDR-TB isolates and drug susceptibility testing (DST) against LNZ is useful in the managementof complicated and drug-resistant cases. However, further studies could identify other possiblegenetic mechanisms of resistance in TB.

کلیدواژه ها:

Mycobacterium tuberculosis ، multidrug-resistance ، linezolid ، mutation ، minimuminhibitory concentration