Novel inhibition of Staphylococcus aureus sortase A by plantamajoside: implications for controlling multidrug-resistant infections

In confronting the significant challenge posed by multidrug-resistant (MDR) pathogens, particularly methicillin-resistant Staphylococcus aureus (MRSA), the development of innovative anti-infective strategies is essential. Our research focuses on sortase A (SrtA), a vital enzyme for anchoring surface proteins in S. aureus. We discovered that plantamajoside (PMS), a phenylpropanoid glycoside extracted from Plantago asiatica L. (Plantaginaceae), acts as an effective and reversible inhibitor of SrtA, with a notable IC50 value of 22.93 µg/mL. This breakthrough provides a novel approach to combat both resistance and virulence in MRSA. PMS significantly inhibits S. aureus adhesion to fibrinogen, reducing biofilm formation and hindering the anchoring of staphylococcal protein A to the cell wall. Live-dead cell assays demonstrated increased survival rates in PMS-treated MRSA-infected A549 cells. Fluorescence quenching experiments revealed a robust interaction between PMS and SrtA, with mechanistic analyses pinpointing the critical R197 amino acid residue as the target site. In vivo, PMS was highly effective in a Galleria mellonella infection model, reducing mortality rates in MRSA-infected larvae. Additionally, PMS demonstrated therapeutic efficacy in a mouse pneumonia model, improved survival rates, reduced the bacterial load in pulmonary tissues, and mitigated lung damage. These results validate PMS as a promising compound to mitigate MRSA virulence and thwart resistance by targeting SrtA. This study highlights PMS as a leading candidate for controlling MRSA infections, showing the potential of targeting specific bacterial mechanisms in the fight against MDR infections.