Gram-positive bacteria employ surface proteins to bind to host tissues, to escape from innate and acquired immune responses, or to invade host epithelia and immune cells. Surface proteins of Staphylococcus aureus are anchored to the cell wall envelope by a mechanism requiring both an N-terminal signal peptide and a C-terminal sorting signal with an LPXTG motif. Sortase A (SrtA), a membrane anchored transpeptidase, cleaves the LPXTG motif of the sorting signal between its threonine (T) and glycine (G) residues and tethers the C-terminal carboxyl group of surface proteins to the amino group of cell wall cross-bridges within the lipid II peptidoglycan precursor. The product of this reaction is subsequently incorporated into the cell wall envelope via the transpeptidation and transglycosylation reactions of peptidoglycan synthesis. S. aureus mutants lacking the srtA gene display significant defects in the pathogenesis of animal disease. The genome of S. aureus encodes two sortase genes, each of which provide distinct anchoring mechanisms for defined sets of surface proteins. The genomes of some gram-positive microbes harbor additional sortase genes that provide for the assembly of pili on the surface of C. diphtheria, E. faecalis, S. agalactiae, A. naeslundii, C. perfringens and perhaps other pathogens. Experimental work in this research proposal tests three general hypotheses: (i) Inhibitors of sortases may be useful for the treatment of bacterial infectious diseases, (ii) The genes and gene products involved in surface protein transport and anchoring to the cell wall envelope may be identified using systematic genetic analysis, (iii) Pilus formation in gram-positive bacteria involves three unique sortase-mediated reactions that can be characterized by revealing the molecular structures of trans-peptidation reaction products.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI038897-11
Application #
6879274
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Program Officer
Peters, Kent
Project Start
1996-02-01
Project End
2010-01-31
Budget Start
2005-02-01
Budget End
2006-01-31
Support Year
11
Fiscal Year
2005
Total Cost
$376,210
Indirect Cost
Name
University of Chicago
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Winstel, Volker; Missiakas, Dominique; Schneewind, Olaf (2018) Staphylococcus aureus targets the purine salvage pathway to kill phagocytes. Proc Natl Acad Sci U S A 115:6846-6851
Yu, Wenqi; Missiakas, Dominique; Schneewind, Olaf (2018) Septal secretion of protein A in Staphylococcus aureus requires SecA and lipoteichoic acid synthesis. Elife 7:
Bobrovskyy, Maksym; Willing, Stephanie E; Schneewind, Olaf et al. (2018) EssH peptidoglycan hydrolase enables Staphylococcus aureus type VII secretion across the bacterial cell wall envelope. J Bacteriol :
Sun, Yan; Emolo, Carla; Holtfreter, Silva et al. (2018) Staphylococcal protein A contributes to persistent colonization of mice with Staphylococcus aureus. J Bacteriol :
Ohr, Ryan Jay; Anderson, Mark; Shi, Miaomiao et al. (2017) EssD, a Nuclease Effector of the Staphylococcus aureus ESS Pathway. J Bacteriol 199:
Anderson, Mark; Ohr, Ryan Jay; Aly, Khaled A et al. (2017) EssE Promotes Staphylococcus aureus ESS-Dependent Protein Secretion To Modify Host Immune Responses during Infection. J Bacteriol 199:
Nygaard, Tyler K; Kobayashi, Scott D; Freedman, Brett et al. (2016) Interaction of Staphylococci with Human B cells. PLoS One 11:e0164410
Missiakas, Dominique; Schneewind, Olaf (2016) Staphylococcus aureus vaccines: Deviating from the carol. J Exp Med 213:1645-53
Chan, Yvonne G Y; Frankel, Matthew B; Missiakas, Dominique et al. (2016) SagB Glucosaminidase Is a Determinant of Staphylococcus aureus Glycan Chain Length, Antibiotic Susceptibility, and Protein Secretion. J Bacteriol 198:1123-36
Kim, Hwan Keun; Falugi, Fabiana; Missiakas, Dominique M et al. (2016) Peptidoglycan-linked protein A promotes T cell-dependent antibody expansion during Staphylococcus aureus infection. Proc Natl Acad Sci U S A 113:5718-23

Showing the most recent 10 out of 95 publications