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Regulation of Peptidoglycan Precursor Synthesis and Maturation in the Pathogenic Bacterium Streptococcus Pneumoniae

出版	Indiana University, 2023
URL	http://books.google.com.hk/books?id=cAg10AEACAAJ&hl=&source=gbs_api

註釋Streptococcus pneumoniae (pneumococcus) is an opportunistic pathogen that has acquired resistance to a broad range of antibiotics and is classified as a “superbug.” Understanding peptidoglycan (PG) cell wall synthesis in S. pneumoniae is necessary for the development of effective new treatments. I focused on the regulators of PG synthesis: GpsB, StkP, IreB, and MacP. GpsB is an essential regulator of PG synthesis, as its depletion leads to cell enlargement, elongation, and lysis. GpsB is also an activator of StkP (Ser/Thr protein kinase) activity in S. pneumoniae, which phosphorylates multiple PG synthesis-associated proteins. I assisted in the isolation and extended characterization of spontaneous mutants that grew in the absence of GpsB or StkP. gpsB or stkP suppressor mutations either: (i) changed PhpP phosphatase and restored protein phosphorylation; (ii) increased levels of MurZ and MurA, which catalyze the first committed step in PG precursor synthesis; (iii) changed MurZ; or (iv) changed IreB, which is a substrate of the StkP Ser/Thr kinase. My work further showed that IreB phosphorylation is the missing link between the two mechanisms that make GpsB and StkP essential in S. pneumoniae. IreB is phosphorylated by StkP at a single Thr residue in approximately 90% of exponentially growing WT cells. IreB interacts directly with MurZ and MurA and forms complexes with StkP and GpsB. Unphosphorylated IreB negatively regulates MurZ and MurA enzyme activity but not their amounts, thereby maintaining optimal pneumococcal PG synthesis and growth. Together, my study revealed that regulation of MurZ and MurA activity by IreB is the only essential requirement for StkP-mediated protein phosphorylation in growing S. pneumoniae cells. In a second project, I studied the importance of another substrate of StkP, MacP, which is a positive regulator of the Class A penicillin-binding protein aPBP2a in S. pneumoniae. This study showed that MacP activity is independent of MacP phosphorylation but is dependent on the MacP transmembrane domain, which is required for aPBP2a activation. These findings contribute to our understanding of the regulation of PG precursor synthesis and maturation.