In addressing the formidable challenge posed by methicillin-resistant Staphylococcus aureus (MRSA), this investigation elucidates a novel therapeutic paradigm by specifically targeting the virulence factor sortase A (SrtA) utilizing Tubuloside A (TnA). SrtA plays a critical role in the pathogenicity of MRSA, primarily by anchoring surface proteins to the bacterial cell wall, which is crucial for the bacterium's ability to colonize and infect host tissues. By inhibiting SrtA, TnA offers a novel and distinct strategy compared to traditional antibiotics. TnA significantly impedes Staphylococcus aureus' adherence to fibrinogen, notably disrupting biofilm development and the integration of staphylococcal protein A (SpA) into the cell wall. Enhanced survival in MRSA-infected A549 cells treated with TnA was demonstrated by live-dead cell assays, confirming its efficacy. The interaction between TnA and SrtA, as indicated by fluorescence quenching and molecular docking studies, shows that TnA has a targeted mechanism of action. Notably, TnA exhibited significant efficacy in reducing MRSA pathogenicity, as demonstrated in a murine pneumonia model. Treatment with TnA resulted in a marked decrease in the bacterial load and improved survival in infected mice. This research highlights the potential of targeting specific bacterial virulence factors as an effective strategy against antibiotic-resistant pathogens and paves the way for the development of innovative antivirulence therapies.
Keywords: Antivirulence; Methicillin-resistant Staphylococcus aureus; Sortase A; Tubuloside A.
© 2025. The Author(s), under exclusive licence to Springer Nature B.V.