Targeted Sortase A Inhibition by Novel Peptidomimetic Antivirulents against Staphylococcal Infections

Abstract Antibiotic resistance is a critical public health issue, causing resistant bacterial strains to be increasingly difficult to control. Antivirulence therapies, which target bacterial virulence factors rather than kill bacteria, present a promising approach. Sortase enzymes, particularly SrtA, are crucial for Gram-positive bacterial virulence by anchoring surface proteins essential for bacterial adhesion and biofilm formation to the bacterial outer cell wall. This study evaluates the selectivity of the peptidomimetic inhibitor BzLPRDSar towards various Gram-positive bacteria. The BzLPRDSar significantly inhibited biofilm formation in multidrug-resistant S. aureus and S. epidermidis . Conversely, it showed variable and generally lower selectivity to Gram-positive species such as E. faecalis, B. cereus and S. agalactiae . The selectivity towards Staphylococcus species is attributed to conserved structural elements in the SrtA enzyme, particularly the β7/β8 loop region with a key tryptophan, likely facilitating strong binding interactions with the inhibitor. Importance This study addresses the pressing issue of antibiotic resistance by exploring antivirulence therapy as an innovative alternative to conventional antibiotics, focusing on inhibiting bacterial virulence rather than bacterial growth. By evaluating the selectivity of the peptidomimetic inhibitor BzLPRDSar against various Gram-positive bacteria, the study highlights its potent selectivity in inhibiting biofilm formation in multidrug-resistant S. aureus and S. epidermidis . The findings underscore the potential of targeting conserved structural elements in bacterial Sortase enzymes, particularly in Staphylococcal species, to develop more selective and effective antivirulence therapies.