| Summary: | Despite scattered studies that have reported mutations in the <i>tet</i>(A) gene potentially linked to tigecycline resistance in clinical pathogens, the detailed function and epidemiology of these <i>tet</i>(A) variants remains limited. In this study, we analyzed 64 <i>Escherichia coli</i> isolates derived from MacConkey plates supplemented with tigecycline (2 μg/mL) and identified five distinct <i>tet</i>(A) variants that account for reduced sensitivity to tigecycline. In contrast to varied tigecycline MICs (0.25 to 16 μg/mL) of the 64 <i>tet</i>(A)-variant-positive <i>E. coli</i> isolates, gene function analysis confirmed that the five <i>tet</i>(A) variants exhibited a similar capacity to reduce tigecycline sensitivity in DH5α carrying pUC19. Among the observed seven non-synonymous mutations, the V55M mutation was unequivocally validated for its positive role in conferring tigecycline resistance. Interestingly, the variability in tigecycline MICs among the <i>E. coli</i> strains did not correlate with <i>tet</i>(A) gene expression. Instead, a statistically significant reduction in intracellular tigecycline concentrations was noted in strains displaying higher MICs. Genomic analysis of 30 representative <i>E. coli</i> isolates revealed that <i>tet</i>(A) variants predominantly resided on plasmids (<i>n</i> = 14) and circular intermediates (<i>n</i> = 13). Within China, analysis of a well-characterized <i>E. coli</i> collection isolated from pigs and chickens in 2018 revealed the presence of eight <i>tet</i>(A) variants in 103 (4.2%, 95% CI: 3.4–5.0%) isolates across 13 out of 17 tested Chinese provinces or municipalities. Globally, BLASTN analysis identified 21 <i>tet</i>(A) variants in approximately 20.19% (49,423/244,764) of <i>E. coli</i> genomes in the Pathogen Detection database. These mutant <i>tet</i>(A) genes have been widely disseminated among <i>E. coli</i> isolates from humans, food animals, and the environment sectors, exhibiting a growing trend in <i>tet</i>(A) variants over five decades. Our findings underscore the urgency of addressing tigecycline resistance and the underestimated role of <i>tet</i>(A) mutations in this context.
|
|---|
