Phylogenetic diversification and fitness trade-offs of TetA variants in mediating eravacycline resistance in <i>Klebsiella pneumoniae</i>

The role of TetA variants in mediating tigecycline and eravacycline resistance in <i>Klebsiella pneumoniae</i> remains a critical area of investigation. However, there has been a lack of systematic characterization of the epidemiology, resistance phenotypes, and fitness costs of TetA variants. Here, we identified 28 TetA variants in <i>K. pneumoniae</i> from the National Center for Biotechnology Information database from 824 isolates, categorizing them into three phylogenetically distinct clades. Among these, four variants were shown to mediate eravacycline resistance, with concurrent but variable effects on tigecycline susceptibility. Notably, these resistance-conferring variants exhibited limited dissemination across clinical and environmental strains. Analyses revealed that their expression imposes a significant fitness cost, markedly reducing bacterial tolerance to the clinical disinfectant H₂O₂ and an environmental heavy metal cadmium-a trait critical for survival under ecological stress. This trade-off likely explains the limited prevalence of these variants despite their resistance phenotypes. Our findings highlight the evolutionary constraints affecting the spread of TetA-mediated antibiotic resistance and underscore the need for One Health-driven surveillance to monitor variants with potential risk in human, animal, and environmental reservoirs. This work provides novel insights into the interplay between resistance determinants and bacterial adaptability, offering a framework for predicting resistance dynamics in <i>K. pneumoniae</i> within the context of interconnected ecological and clinical ecosystems.