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 ss-lactams, so-called methicillin-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 ss-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.
|David, Michael Z; Daum, Robert S; Bayer, Arnold S et al. (2014) Staphylococcus aureus bacteremia at 5 US academic medical centers, 2008-2011: significant geographic variation in community-onset infections. Clin Infect Dis 59:798-807|