Staphylococcal accessory regulator SarA-mediated modulation of autolysis and surface charge enables <i>Staphylococcus aureus</i> to evade vancomycin killing

<i>Staphylococcus aureus</i> is a major source of community and nosocomial infections. Due to the extensive application of antibiotics, <i>S. aureus</i> has developed resistance to antibiotics, especially vancomycin, making clinical treatment challenging. Staphylococcal accessory regulator A (SarA) modulates <i>S. aureus</i> virulence by regulating the principal virulence factors. However, its role in vancomycin resistance remains largely unknown. Herein, we found that SarA not only reduces the susceptibility of <i>S. aureus</i> to vancomycin by directly inhibiting the expression of autolysis-related genes, but also enhances resistance to vancomycin by negatively regulating the transcription of an ATP-binding cassette (ABC) transporter, ABC-like, thereby altering the bacterial surface charge and reducing vancomycin's binding efficiency to the cell wall. Moreover, the regulation of antibiotic resistance by SarA is strain-dependent. Our study uncovers the roles of SarA in regulating vancomycin resistance, providing potential targets and ideas for the prevention and control of vancomycin-intermediate <i>S. aureus</i> infections.IMPORTANCE<i>Staphylococcus aureus</i> poses a major threat to public health due to its increasing resistance to vancomycin, a last-line antibiotic. This study reveals that Staphylococcal accessory regulator A regulates vancomycin resistance in <i>S. aureus</i> by suppressing genes related to autolysis and negatively regulating an ATP-binding cassette (ABC) transporter (ABC-like). This regulation of the transporter reduces the bacterial surface charge, impairing the ability of vancomycin to bind to the cell wall. These findings suggest a novel mechanism of antibiotic resistance in <i>S. aureus</i> and identify potential targets for combating vancomycin-intermediate <i>S. aureus</i> infections.