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

TL;DR

This study shows how a regulator in Staphylococcus aureus helps the bacteria resist vancomycin by altering its cell surface and reducing antibiotic binding.

Contribution

The study reveals a novel mechanism by which SarA modulates vancomycin resistance through autolysis suppression and ABC transporter regulation.

Findings

SarA reduces vancomycin susceptibility by inhibiting autolysis-related genes.

SarA enhances resistance by altering surface charge via ABC-like transporter regulation.

The effect of SarA on antibiotic resistance is strain-dependent.

Abstract

Staphylococcus aureus is a major source of community and nosocomial infections. Due to the extensive application of antibiotics, S. aureus has developed resistance to antibiotics, especially vancomycin, making clinical treatment challenging. Staphylococcal accessory regulator A (SarA) modulates S. aureus 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 S. aureus 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 S. aureus infections.

Staphylococcus aureus 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 S. aureus 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 S. aureus and identify potential targets for combating vancomycin-intermediate S. aureus infections.

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