Understanding bacterial responses to antibiotics is essential for identifying resistance mechanisms and developing novel therapies. This study evaluated the resistance of Staphylococcus aureus (S. aureus) to fusidic acid (FD) in 100 patients with skin and soft tissue infections (SSTIs), revealing susceptibility to FD despite resistance to other antibiotics. Through adaptive laboratory evolution, we developed a highly FD-resistant strain, E10, and identified three gene mutations (fusA, BPENGOFF-00211, and rplF) using whole-genome sequencing. The fusA mutation was the primary contributor to resistance. Furthermore, the evolved fusA mutant strain (H457Y) displayed impaired coagulation function and reduced growth rates. We also analyzed the metabolomic profiles of ancestral ATCC 25923 and evolved E10 strains, both treated and untreated with FD, revealing that the fusA gene can independently induce metabolic reprogramming. These changes primarily impacted pathways involved in central carbon metabolism, nucleotide metabolism, and amino acid synthesis. This study highlights the complexity of FD resistance in S. aureus and offers insights into the metabolic pathways associated with antibiotic resistance. A novel perspective on the antibiotic fusidic acid from a metabolic viewpoint.
[1]Shanghai Jiao Tong Univ, Sch Agr & Biol, Dept Anim Sci, Shanghai Key Lab Vet Biotechnol, 800 Dongchuan Rd, Shanghai 200240, Peoples R China.
[2]Shanghai Jiao Tong Univ, Collaborat Innovat Ctr Agriseeds, Sch Agr & Biol, Shanghai 200240, Peoples R China.
[3]Tianjin Acad Tradit Chinese Med Affiliated Hosp, Dept Clin Lab, Tianjin 300120, Peoples R China.
(8.0+极速模式)