In Silico-Guided Discovery and In Vitro Evaluation of Natural Sortase A Inhibitors to Fight Multidrug-Resistant Staphylococcus aureus

Antimicrobial resistance poses a serious global health
threat.
Sortase A (SrtA), a membrane-bound cysteine transpeptidase responsible
for anchoring key virulence factors to cell wall of Gram-positive
bacteria, acts as critical driver of pathogenicity. Here, molecular
dynamics simulations were employed to explore SrtA conformational
flexibility and guide a structure-based virtual screening of approximately
300,000 natural compounds. Seven structurally diverse hits were selected
based on their ability to bind the multiple conformations and their
favorable docking scores. Drug-likeness and pharmacokinetic properties
were predicted and compared with those of agents currently used against
multidrug-resistant Staphylococcus aureus, revealing that the identified compounds obey both Lipinski’s
and Muegge’s rules. In vitro assays confirmed the SrtA inhibitory
activity of the two compounds in the low micromolar range. Noteworthy,
both compounds significantly reduced S. aureus adhesion to fibrinogen, suggesting functional inhibition of endogenous
bacterial SrtA. These findings support the potential of these natural
scaffolds as antivirulence drug candidates.