Interaction and interdependency of GlmM and DacA - two essential enzymes required for methicillin resistance in Staphylococcus aureus

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Staphylococcus aureus is frequently found on the skin, nares or other mucosal surfaces of healthy individuals without causing any symptoms or harm. However, S. aureus can also cause a wide variety of infections ranging from small skin infections to life-threatening invasive diseases. Alarmingly, many S. aureus strains have acquired resistance to multiple antimicrobials and as a result S. aureus is still one of the leading causes of antibiotic-resistant healthcare-associated infections worldwide. The resulting difficulty in treating these infections is a major public health concern. Therefore, it is of interest to study biosynthesis pathways and enzymes that are required for bacterial growth to ultimately develop new antimicrobials. The purpose of this study is to characterize the interaction and interdependency of the two staphylococcal enzymes GlmM and DacA. Both enzymes are extremely important for the growth of S. aureus. At the first glance there is no apparent connection between them as GlmM is required for the production of an essential cell wall precursor and DacA is responsible to the production of a recently discovered signalling nucleotide c-di-AMP. However, recent work has indicated that there is a direct protein/protein contact between these two enzymes, suggesting that the pathways that they regulate are somehow interconnected. DacA and GlmM are therefore potentially central players in coordinating the synthesis of the cell wall polymer peptidoglycan with pathways that are regulated by c-di-AMP. The aims of this project are to provide an image of the DacA/GlmM complex in order to show exactly how these two proteins interact, find out how the activity of one enzyme influences the activity of the other and how this interaction affects the growth and methicillin resistance of the cell. In summary, the work will yield valuable information on the interdependency of two important bacterial enzymes, which interconnect two essential cellular processes in the Gram-positive bacterial pathogen S. aureus. Due to the direct link of S. aureus to human infection, the output of this work on essential cellular pathways can potentially offer future opportunities for the development of novel therapeutic approaches interfering with the growth of S. aureus and potentially a number of other Gram-positive pathogens.