Staphylococcus aureus infections are a leading cause of healthcare and community associated infections worldwide. Some strains of the pathogen have developed the ability to resist most of the classic antibiotics including penicillins and cephalosporins. There is an urgent need to develop new drugs that work against these resistant strains including methicillin-resistant Staphylococcus aureus, or MRSA.
A promising new set of antibiotic targets has recently been proposed involving the wall teichoic acid biosynthetic pathway of Gram positive pathogens. These long, acidic polymers are synthesized in the cell, transported out and ultimately attached to the growing outer cell-wall protective layer, a process essential to virulence and survival of MRSA in the infected host and in the environment. Small molecule inhibitor screens have identified compounds that block the action of one of these components, TarG/H, an intimately associated pair of membrane localized proteins that transport teichoic acids from the cytosol to the outer cell-wall layer. Learning more about the structure and function of the TarG/H transporter and its partner proteins in the pathway could allow scientists to design drugs that work much more effectively and specifically against Gram positive pathogens such as MRSA.
The goals of my research are therefore to solve the three-dimensional structure of the purified TarG/H transporter in native, mutant and inhibited forms at atomic resolution using X-ray crystallography and secondly, to characterize the molecular details, using single particle cryo-electron microscopy, of how TarG/H binds with other proteins involved in making and transporting the teichoic acid chains to the outer regions of the cell. The ultimate goal of this work is to enable the structure-guided design of potent new antibiotics that block TarG/H action and MRSA virulence.