Prioritizing Staphylococcus aureus Regulatory Elements for Therapeutic Exploitation

Staphylococcus aureus is an important pathogen and can cause a variety of localized and systemic infections. In certain types of infections, most notably osteomyelitis, the efficacy of conventional antibiotic therapy is limited due the S. aureus biofilm. We have previously explored the possibility of targeting genes that regulate biofilm production as a novel means to treat these infections. However, the S. aureus species is genetically and phenotypically diverse. This has made it exceedingly challenging to understand the gene regulation that drives S. aureus pathogenesis. The overarching goal of this study is to identify central regulatory elements that could be exploited therapeutically using regulatory mutants in divergent S. aureus strains and testing their relative capacity to cause disease using animal models of infection. So far, SarA has shown the most promise as a novel therapeutic target for the treatment of acute and chronic S. aureus infections. This is because mutation of sarA limits the accumulation of biofilm, and other virulence factors, to a greater degree any other regulatory element investigated thus far. Importantly, this limitation is directly attributed to the increase in S. aureus proteases that are most abundant in a sarA mutant. Here, we explore the potential of agr, codY, fur, mgrA, msa, rot, sigB, and xerC, each of which has been implicated in biofilm formation, by directly comparing their impact on virulence to that of sarA. Here, we report that mutation of msa, a global virulence regulator and activator of sarA expression, attenuated virulence in a murine model of osteomyelitis which correlated proportionally with increased S. aureus protease production. Additionally, we found that mutation of sarA, codY, and sigB attenuate virulence during murine bacteremia in both the USA300 strain LAC and the USA200 strain UAMS-1, and that the attenuation of these mutants also correlated with elevated levels of protease production. Taken together, these studies provide further evidence that S. aureus must limit the expression of its secreted proteases in order to maintain virulence. Importantly, they provide a logic for targeting central regulatory elements that repress proteases as novel therapeutic strategy to treat different S. aureus infections