Beta-lactones as specific inhibitors of ClpP attenuate the production of extracellular virulence factors of Staphylococcus aureus.

To approach the daunting problem of multidrug resistant bacterial pathogens, a multidisciplinary chemical proteomic strategy was applied and functionalized beta-lactones were identified as potent, cell permeable inhibitors for specific and selective targeting of the key virulence regulator complex ClpP in S. aureus and methicillin resistant S. aureus (MRSA) strains. ClpP represents the central protease complex responsible for the activation of numerous virulence factors including many with devastating effects for human health such as hemolysins, proteases, lipases, and DNases. Although the crucial role of this enzyme was validated by genetic knockouts, no inhibitor has been reported to date. In fact, our most potent inhibitor was able to completely abolish hemolytic and proteolytic activities and showed a dramatic decrease in the activities of virulence associated lipases and DNases. These effects were also observed in a multiresistant strain emphasizing the potential value of such compounds. Targeting this virulence factor may therefore likely represent an attractive strategy for neutralizing the harmful effects of bacterial pathogens and help the host immune response to eliminate the disarmed bacteria. Since ClpP is not essential for viability and highly conserved in many pathogens, our strategy could represent a global approach for the treatment of infectious diseases without the pressing problem of antibiotic pressure and resistance development.