A eukaryotic-like uridyltransferase links cell envelope biogenesis and second messenger signaling in Staphylococcus aureus

About This Grant

PROJECT SUMMARY More deaths worldwide are caused by methicillin-resistant Staphylococcus aureus than by any other antibiotic- resistant bacterial pathogen. S. aureus is commonly found as a commensal on human skin and in nasal passages, but it can become a deadly pathogen when it enters the bloodstream, the lungs, or other parts of the body. Understanding the adaptations that are unique to Staphylococcaceae is crucial for developing strategies to combat S. aureus infections. Because the peptidoglycan cell wall is conserved across bacteria and is a major target for antibiotics, most of the factors involved in cell wall assembly have been studied extensively. However, our preliminary studies have identified in S. aureus a novel uridyltransferase that collaborates with the acetyltransferase domain of the universally conserved enzyme GlmU to make the essential cell wall precursor UDP-N-acetylglucosamine (UDP-GlcNAc). We have found that this uridyltransferase, here named NagU, physically interacts with DacA, the diadenylate cyclase that makes the bacterial second messenger cyclic-di-AMP (c-di-AMP), which regulates ion flux across the membrane to control turgor pressure. We hypothesize that the NagU-DacA complex coordinates peptidoglycan synthesis and turgor pressure regulation. We propose to combine genetics, biochemistry, cell biology, and metabolomics approaches to characterize the cellular roles of NagU and to investigate how its ability to form a complex with DacA impacts peptidoglycan and c-di-AMP synthesis. Because NagU is one of a small number of S. aureus genes with an SOS box, suggesting an interconnection among DNA damage repair, turgor pressure and cell wall integrity, we will also investigate whether cell envelope integrity is connected to SOS-mediated DNA damage repair mechanisms. Our findings will provide fundamental insights into unique aspects of S. aureus physiology that can be exploited to combat antibiotic-resistant infections.