Molecular Mechanism of Staphylococcus xylosus Resistance Against Tylosin and Florfenicol

Purpose: Drug resistance presents an ever-increasing global public health threat that involves all major microbial pathogens and antimicrobial drugs. Strains that are resistant to multiple drugs pose severe clinical problems and cost lives. However, systematic studies on cross-resistance of Staphylococcus xylosus have been missing. Methods: Here, we investigated various mutations in the sequence of ribosomal proteins involved in cross- resistance. To understand this effect on a molecular basis and to further elucidate the role of cross-resistance, we computationally constructed the 3D model of the large ribosomal subunit from S. xylosus as well as its complexes with both tylosin and florfenicol. Meanwhile, all- atom molecular dynamics simulations was used. In addition, the regulation of protein networks also played an essential role in the development of cross-resistance in S. xylosus. Results: We discovered that the minimum inhibitory concentration against both tylosin and florfenicol of the mutant strain containing the insertion L22 97KRTSAIN98 changed dramatically. Further, we found that unique structural changes in the [beta]- hairpin of L22 played a central role in this variant in the development of antibiotic resistance in S. xylosus. The regulation of protein networks also played an essential role in the development of cross-resistance in S. xylosus. Conclusion: Our work provides insightful views into the mechanism of S. xylosus resistance that could be useful for the development of the next generation of antibiotics. Keywords: antimicrobial resistance, Staphylococcus xylosus, cross-resistance evolution, ribosomal protein L22