Wall teichoic acid biosynthesis as a novel antimicrobial target in Staphylococcus aureus

Antibiotic resistance poses a major threat to human health, and invasive methicillin resistant Staphylococcus aureus (MRSA) infections have emerged as a leading cause of life-threatening infections in the United States. MRSA infections already cause more deaths each year in the U.S. than HIV/AIDS (∼20,000 in 2005), and the mortality rate is expected to increase. Resistance has recently appeared to vancomycin, linezolid, and cubucin antibiotics used for the treatment of MRSA infections. These facts underscore the ongoing need for novel compounds and strategies to combat S. aureus infections. The content of this thesis pertains to evaluating a new strategy to treat S. aureus infections by targeting Wall Teichoic Acid (WTA) biosynthesis.;Chapter One provides an introduction into the areas of antibiotic discovery and resistance as well as background information regarding the WTA biosynthesis field of research.;In Chapter Two, the WTA biosynthetic pathway for S. aureus is described. Using a series of genetic and biochemical experiments, we propose and validate a new pathway for S. aureus WTA biosynthesis. Through this work we were able to identify which gene products within the pathway serve as either antivirulence or antibiotic targets. This understanding of the WTA biosynthetic pathway in S. aureus is crucial for the development of this pathway as an antimicrobial target.;Chapter Three discusses the discovery of a small molecule inhibitor, targeting WTA biosynthesis, known as targocil. Targocil is the first reported antibiotic that functions by inhibiting WTA biosynthesis, a long sought after antimicrobial target, and it utilizes a novel mechanism of resistance. Since the pathway is not essential for survival, the easiest route to resistance is to shut off WTA biosynthesis. However, WTA expression is critical for host colonization and infection, and we have shown that targocil escape mutants are attenuated in their pathogenicity.;The work described in these Chapters lays the foundation for determining whether targeting WTA biosynthesis is efficacious in treating S. aureus infections. The hope for this work is to provide lead compounds that will be successful at combating bacterial resistance.