Advisory Committee Chair
Susan Hollingshead
Advisory Committee Members
David Briles
William Benjamin
David Pritchard
Charles Turnbough
Janet Yother
Document Type
Dissertation
Date of Award
2008
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Sortases are transpeptidases that covalently link surface proteins to the stempeptide on the cell wall peptidoglycan of Gram-positive bacteria. This work endeavored to characterize the various sortase enzymes and their effect on the virulence of Streptococcus pneumoniae. The genome of S. pneumoniae may encode up to four sortase enzymes. We found that 38 of 54 strains of serotype 6B clonal complex 14 (CC14) carry the genes for the secondary sortases srtB, srtC, and srtD. The presence of these sortases did not seem to influence the ability of strains within CC14 to infect the nasopharynx, lungs, or blood of strains within CC14; however a mutant deficient in the expression of the srtBCD operon in an unrelated strain, TIGR4, showed increased virulence in an invasive model of infection. Investigation of the primary sortase, SrtA led to the knowledge that it is important for cell wall attachment of several proteins, including β-galactosidase, hyaluronate lyase, and IgA1 protease. SrtA was not required for the surface localization of zinc metalloprotease B (ZmpB). The exact location of the covalent linkage between sorted proteins and the cell wall is still unknown; however we were able to demonstrate that the deletion of the cell wall branching enzyme MurM does not effect the localization of β-galactosidase and hyaluronate lyase activity on the cell surface. This data indicates that SrtA may utilize the free ε-amino group of the lysine found on the pneumococcal stem peptide. Inactivation of SrtA in a mouse model of sepsis resulted in increased virulence relative to the wild-type strain. The srtA mutant strain also exhibited a one log iii increase in the number of colonizing bacteria in a mouse nasopharyngeal colonization model. The results reported in this dissertation suggest a cautionary approach to the use of sortase inhibitors as therapeutics for the treatment of S. pneumoniae.
Recommended Citation
Bennett, Allison E., "Characterization Of Sortase And Its Effect On The Virulence Of Streptococcus Pneumoniae" (2008). All ETDs from UAB. 3665.
https://digitalcommons.library.uab.edu/etd-collection/3665