Conservation and biochemical characterization of the essential Staphylococcus aureus lipoteichoic acid synthase LtaS

Lay Summary:
Staphylococcus aureus is a Gram-positive bacterial pathogen that can cause a variety of infections both in hospital settings as well as in the community. Many antibiotics, which have been successfully used to treat such bacterial infections, kill the bacterium by inhibiting the production of important surface-structures. However, an alarming aspect of staphylococcal infections is that bacteria have acquired resistance to multiple antimicrobials and the infection rate with methicillin-resistant S. aureus strains (MRSA) within the UK is amongst the highest in developed countries. Therefore, it is important to identify and validate alternative ways to inhibit staphylococcal growth. I have recently identified a protein named LtaS, which is required for the synthesis of a surface structure called lipoteichioc acid. Depletion of this protein caused a halt in lipoteichioc acid synthesis and completely blocked staphylococcal growth. These results suggest that LtaS and the lipoteichioc acid synthesis pathway can serve as targets for antibiotic development. This study aims to determine if LtaS is required for growth in other human pathogens. In addition, the proposed work will give insight into the mechanism of action of the enzyme LtaS, which will be of great benefit for the future development of lipoteichioc acid synthesis inhibitors.

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Staphylococcus aureus is a Gram-positive bacterial pathogen that can cause a wide variety of both community- and hospital?acquired infections. A functional cell envelope is necessary for this pathogen to interact with its environment, in particular with tissues of the infected host, and to cause infection. An important structure found within the envelope of Gram-positive bacteria is lipoteichoic acid (LTA) and I have recently identified the enzyme that is required for polyglycerolphosphate LTA synthesis. Depletion of this protein, which was renamed LtaS (for lipoteichoic acid synthase) not only led to a halt in LTA synthesis but also completely blocked staphylococcal growth. These results suggest that LtaS and the LTA synthesis pathway can serve as targets for antibiotic development, similar to the primary wall polymer peptidoglycan, which is the target of penicillin and other antibiotics. This study aims to investigate the phylogenetic distribution, structure, and enzymatic properties of LtaS. Execution of these aims will give insight into the mechanism of action of the enzyme LtaS and will be of great benefit for the development of LTA synthesis inhibitors. It is specifically proposed to:

Aim 1: Analyze the requirement of LtaS for growth and LTA synthesis in methicillin-resistant S. aureus strains and other Gram-positive pathogens
Aim 2: Investigate the role of LtaS in membrane lipid turnover
Aim 3: Determine the structure of LtaS and residues required for enzyme function