Abstract
The emergence of plasmid-mediated tigecycline resistance gene tet(X4) poses a challenging threat to public health. Based on the analysis of tet(X4)-positive plasmids in the NCBI database, we found that the IncX1-type plasmid is one of the most common vectors for spreading tet(X4) gene, but the mechanisms by which these plasmids adapt to host bacteria and maintain the persistence of antibiotic resistance genes (ARGs) remain unclear. Herein, we investigated the underlying mechanisms of how host bacteria modulate the fitness cost of IncX1 plasmids carrying tet(X4) gene. Interestingly, we found that the tet(X4)-bearing IncX1 plasmids encoding H-NS protein imposed low or no fitness cost in Escherichia coli and Klebsiella pneumoniae; instead, they partially promoted the virulence and biofilm formation in host bacteria. Regression analysis revealed that the expression of hns gene in plasmids was positively linked to the relative fitness of host bacteria. Furthermore, when pCE2::hns was introduced, the fitness of tet(X4)-positive IncX1 plasmid pRF55-1 without hns gene was significantly improved, indicating that hns mediates the improvement of fitness. Finally, we showed that the expression of hns gene is negatively correlated with the expression of tet(X4) gene, suggesting that the regulatory effect of H-NS on adaptability may be attributed to its inhibitory effect on the expression of ARGs. Together, our findings suggest the important role of plasmid-encoded H-NS protein in modulating the fitness of tet(X4)-bearing IncX1 plasmids, which shed new insight into the dissemination of tet(X4) gene in a biological environment.
Highlights
Antibiotic resistance has constituted a growing threat to global public health
We found that the plasmids with multiple replicon types were the most common in tet(X4)-positive plasmids, while IncX1 plasmids were dominant in single replicon plasmid types, accounting for 72.2% (Figure 1A)
Considering that fitness cost elicited by resistance plasmids directly affects the dissemination of resistance genes, we hypothesize that Histone-like nucleoid structuring (H-NS) protein may modulate the fitness of host bacteria, which is critical for the transmission of plasmids
Summary
Antibiotic resistance has constituted a growing threat to global public health. According to the data released by WHO, it is estimated that by 2050, the number of human deaths caused by multiple-drug resistance will increase to 10 million, surpassing the number of cancer deaths and becoming one of the leading causes of human death worldwide (Kuehn, 2011). Because of the widespread distribution of carbapenem resistance gene, blaNDM (Nordmann et al, 2011), and. With the emergence of high-level tigecycline resistance gene tet(X3/X4) (He et al, 2019; Sun et al, 2019), few choices were left for clinicians from the traditional antibiotic pipeline. The high expression of plasmid-related genes would impose additional energy and metabolic burden to host bacteria, thereby resulting in fitness cost (San Millan and MacLean, 2017). Since its first description in China in 2019, tet(X4)-bearing plasmids have been found worldwide (Ding et al, 2020; Zhang et al, 2020; Mohsin et al, 2021). IncX1 plasmid is one of the important vectors of tet(X4) gene (Li et al, 2020b), but the physiological mechanisms of widespread of tet(X4)-harboring IncX1 plasmids in different host strains are still unclear
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