Regulation of Capsule Polysaccharides
The capsule polysaccharide (CPS) produced by Streptococcus pneumonia and Staphylococcus aureus is a key virulence factor that confers resistance to phagocytosis, and impacts on colonisation, systemic invasion and growth. The production and cell wall ligation of CPS in nearly all S. pneumonia serotypes is dependent on the four proteins (CpsA, CpsB, CpsC, CpsD), and the overall the biosynthesis of the CPS repeat unit mechanism has much in common with lipopolysaccharide O antigen biosynthesis. The biosynthesis and regulation of CPS production, and the properties of CpsC, CpsB, and CpsD are being investigated in collaboration with Dr Alistair Standish.
The CpsB, CpsB, CpsD proteins interact in a cycle of autophosphorylation (mediated by CpsC interacting with CpsD, a protein tyrosine kinase) and de-phoshorylation (mediated by CpsB, a protein tyrosine kinase), as reviewed by Standish et al (2012b). These proteins are targets for development of drugs that prevent infection through inhibition of CPS production, as shown for CpsB by Standish et al (2012a).
Relevant Publications (Since 1997)
Standish, A.J., and Morona, R. (2013) The role of bacterial protein tyrosine phosphatases in the regulation of the biosynthesis of secreted polysaccharides. Antioxid Redox Signal. 2013 Dec 2. [Epub ahead of print]
Standish, A.J., Salim, A.A., Capon, R.J., and Morona R. (2013) Dual inhibition of DNA polymerase PolC and protein tyrosine phosphatase CpsB uncovers a novel antibiotic target. Biochem Biophys Res Commun. 430:167-172.
Ericsson DJ, Standish A, Kobe B, and Morona R. (2012b) Wzy-dependent bacterial capsules as potential drug targets. Curr Drug Targets. Curr Drug Targets. 13:1421-1431.
Standish, A.J, Salim, A.A., Capon, R.J, and Morona, R. (2012a) "Chemical inhibition of bacterial protein tyrosine phosphatase suppresses capsule production." PLoS ONE 7(5): e36312. doi:10.1371/journal.pone.0036312.
Byrne, J., Morona, J,K., Paton, J.C., and Morona, R. (2011) "Identification of Streptococcus pneumoniae Cps2C Residues that affect capsular polysaccharide polymerisation, cell wall Ligation and Cps2Dphosphorylation." J. Bacteriol. 193:2341-2346.
Morona, J.K., Morona, R., Paton, J.C. (2006) "Attachment of capsular polysaccharide to the cell wall of Streptococcus pneumoniae type 2 is required for invasive disease." Proc Natl Acad Sci U. S. A. 103: 8505-8510.
Morona, J.K., Miller, D.C., Morona, R., and James C. Paton, J.C. (2004) "The effect of mutations in the conserved genes cps2A, cps2B and cps2D on virulence in Streptococcus pneumoniae." J. Infect. Dis. 189:1905-1913.
Morona, J.K., Morona, R., Miller, D.C., and Paton, J.C. (2003) "Mutational analysis of the carboxy-terminal [YGX]4 repeat domain of CpsD, an autophosphorylating tyrosine kinase required for capsule biosynthesis in Streptococcus pneumoniae." J. Bacteriol. 185: 3009-3019.
Morona, J.K. Morona, R., Miller, D.C., and Paton, J.C. (2002) "The Streptococcus pneumoniae capsule biosynthesis protein CpsB is a novel manganese-dependent phosphotyrosine-protein phosphatase." J. Bacteriol. 184: 577-583.
Morona, J.K., Paton, J., Miller, D., and Morona, R. (2000) "Tyrosine phosphorylation of CpsD negatively regulates capsule polysaccharide production in Streptococcus pneumoniae. " Mol. Microbiol. 35: 1431-1442
Morona, J.K., Morona, R. and Paton, J.C. (1999) "Analysis of the 5' portion of the type 19A capsule locus identifies two classes of cpsC, cpsD and cpsE genes in Streptococcus pneumoniae." J. Bacteriol. 181: 3599-3605
Morona, J.K., Miller, D.C., Coffey, T.J., Vinurampulee, C.J., Spratt, B.G., Morona, R., and Paton, J.C. (1999) "Molecular and genetic characterisation of the capsule biosynthesis locus of Streptococcus pneumoniae type 23F." Microbiol. 145: 781-789
Coffey, T.J., Enright, M.C., Daniels, M., Morona, J.K., Morona, R., Hryniewicz, V., Paton, J.C., and Spratt, B.G. (1998) "Recombinational exchanges at the capsular polysaccharide biosynthetic locus lead to frequent serotype changes among natural isolates of Streptococcus pneumoniae". Mol. Microbiol. 27: 73-84.
Paton, J.C., Morona, J.K., and Morona, R. (1997) "Characterisation of the capsular polysaccharide biosynthesis locus of Streptococcus pneumoniae type 19F". Microbial Drug Resistance 3: 89-99.
Morona, J.K., Morona, R., and Paton, J.C. (1997) "Analysis of the genes encoding biosynthesis of type 19F capsule from Streptococcus pneumoniae". Mol. Microbiol. 23: 751-763.