Staphylococcus aureus is a well-adapted human parasite that is both a commensal and an important pathogen. It is responsible for a wide variety of infectious diseases that range from minor skin abscesses to severe infections and toxinoses requiring hospitalization. S. aureus strains resistant to nearly all -lactams, so-called methicilln-resistant S. aureus (MRSA), are a leading cause of healthcare associated and, since the 1990s, community-associated infections. This epidemic of MRSA infections has enhanced the urgency to identify alternative antimicrobial agents for successful treatment. The present application concerns the vra operon that is conserved among S. aureus strains and encodes a three-component signal transduction system that senses and responds to cell-wall stress elicited by clinically important antimicrobials. Experimental interruption of the vra operon in a MRSA strain dramatically decreases the minimal inhibitory concentration of oxacillin, a methicillin congener, in MRSA strains. Thus, we wish to explore the idea that vra operon inhibition by small molecules may enhance the ability of -lactam antibiotics, such as oxacillin, to kill MRSA strains and treat infections caused by them. Since vra operon expression is induced by cell-wall agents from many chemical classes, the oxacillin potentiators we identify may also enhance activity of a wide variety of other antimicrobials that interfere with cell-wall synthesis such as vancomycin, cationic peptides and daptomycin.
New antibiotics are needed to treat antibiotic resistant Staphylococcus aureus infections. We have proposed to inhibit a signal transduction system that senses cell wall stress and is necessary for expression of antibacterial resistance phenotypes.
