<p>Genetic and Virulence Characteristics of Linezolid and Pretomanid Dual Drug-Resistant Strains Induced from <em>Mycobacterium tuberculosis</em> in vitro</p>

Abstract

Purpose: Linezolid (LZD) and pretomanid (PA-824) are promising candidates in regimens for the treatment of drug-resistant tuberculosis. However, research on LZD and PA-824 dual drug-resistant (LPDR) strains is rarely reported. This study aimed to investigate the genotypic and virulence characteristics of LPDR strains. Methods: To obtain the LPDR strains (marked as LP or PL strains), we used a two-way induction method, namely, we first induced LZD-or PA-824-resistant mutants from the parental Mycobacterium tuberculosis (MTB) strain H37Rv in vitro, then we obtained the LPDR strains from induction of LZD-or PA-824-resistant mutants. Mutations in rplC, rrl, or ddn and fgd1 were identified in all mutants. To investigate the virulence of these strains, six strains were selected as representative strains, including LZD-resistant strains, PA-824resistant strains and LPDR strains. We performed the animal survival study as virulence of MTB can be measured as survival time of an animal after being infected. Results: We induced 38 mutant strains of LZD and PA-824 mono or dual drug resistance from H37Rv in vitro. The mutation frequency of rplC (C154R) gene in LPDR strains was 100% and 86%, respectively. In the animal survival study, animals infected with different drug-resistant strains survived significantly longer than those infected with H37Rv; animals infected with LPDR strains and PA-824-resistant strains survived similarly and both of which survived significantly shorter than those infected with LZD-resistant strains. Conclusion: Our study showed that rplC gene had a high mutation frequency in LPDR strains. The virulence of LPDR strains was similar to PA-824-resistant strains, and the virulence of the LZD-resistant strains was weaker than PA-824-resistant strains.

Linezolid resistance among multidrug-resistant Mycobacterium tuberculosis clinical isolates in Iran

“…LNZ has exhibited an excellent anti-mycobacterial effect and several studies have shown that it is an effective third-line antibiotic for the treatment of the MDR-and XDR-TB patients, with favorable outcomes [11][12][13]. It is now classified as group A, the preferred drug group for MDR-TB and rifampin-resistant TB treatment that plays a critical role in the treatment of drug-resistant TB [7,14].…”