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

In confronting the significant challenge posed by multidrug-resistant (MDR) pathogens, particularly methicillin-resistant <i>Staphylococcus aureus</i> (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 <i>S. aureus</i>. We discovered that plantamajoside (PMS), a phenylpropanoid glycoside extracted from <i>Plantago asiatica L</i>. (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 <i>S. aureus</i> 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. <i>In vivo</i>, PMS was highly effective in a <i>Galleria mellonella</i> 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.IMPORTANCEThe increasing issue of antibiotic resistance, particularly in methicillin-resistant <i>Staphylococcus aureus</i> (MRSA), demands innovative solutions. Our study presents plantamajoside (PMS) as a novel inhibitor of sortase A (SrtA), a key enzyme in <i>S. aureus</i> pathogenicity. By targeting SrtA, PMS shows promise in curbing the ability of MRSA to adhere, invade, and form biofilms, thereby reducing its virulence without exerting selective pressure for resistance. This research is significant because it introduces a potential new strategy in the antimicrobial arsenal, aligning with the global effort to combat drug-resistant infections. This study is crucial because it identifies a natural compound that can reduce the harmful effects of MRSA, a type of bacteria that is very hard to treat owing to resistance to many antibiotics. This discovery could lead to new treatments that are less likely to cause bacteria to become resistant, which is a major win in the fight against infections that are difficult to cure.