Beta-Lactones as Specific Inhibitors of ClpP Attenuate the Production of Extracellular Virulence Factors of Staphylococcus aureus
With the evolution of multidrug resistant bacterial pathogens, infectious diseases pose once again a serious threat to public health. Especially the opportunistic pathogen Staphylococcus aureus has gained importance through the dramatically increasing appearance of methicillin-resistant (MRSA) strains in hospitals and the recent emergence of epidemic community-associated MRSA infections. Major reasons for this daunting problem are the excessive use of conventional antibiotics, the limited number of essential cellular targets addressed by these compounds, and their paramount selective pressure exerted on bacterial viability leading to resistance development. Here we introduce an alternative strategy based on functionalized beta-lactones to target bacterial virulence rather than viability. A central role in S. aureus virulence regulation can be attributed to the caseinolytic protein protease (ClpP), a phylogenetically highly conserved serine protease that was found to be crucial for virulence of many bacterial pathogens.