Discovery of a New Class of Sortase A Transpeptidase Inhibitors to Tackle Gram-positive Pathogens: 2-Phenylhydrazonoalkanoic Acid Derivatives

There is an urgent need of anti-virulence agents effective in the prevention or eradication of biofilms that are intrinsically resistant to conventional antibiotics. If we consider that the first step of staphylococcal pathogenesis and of biofilm formation is the bacterial adhesion, promoted by the surface exposed proteins at the cell wall, we believe that new anti-virulence agents could be developed by using as a target the Sortase A (SrtA), the enzyme responsible of linking surface exposed proteins to peptidoglycan. Therefore, SrtA inhibitors could act as anti-adhesion agents useful to prevent Gram positive virulence mechanisms as well as a virulence mechanism based on biofilm formation. Starting from these consideration and in continuing our research work on antibacterial/antibiofilm agents, we thought it was of interest to obtain novel SrtA inhibitors, showing a molecular diversity than the known ones.The esters and the acids were tested for their inhibitory activity on SrtA, utilizing the FRET technics (Fluorescenze Resonance Energy Transfer) [1]. Some of them showed IC50 values in the range 50-100 μM. For a preliminary assessment of antivirulence properties the most active SrtA inhibitors were tested for their ability to interfere with biofilm formation of S. aureus ATCC 29213, S. aureus ATCC 25923, S.aureus ATCC 6538 and S. epidermidis RP62A. We found that the above derivatives interfere with biofilm formation