Grants and Contracts Details
Human Group IIA secreted phospholipase A2 (hGIIA) is a highly cationic small protein important for the innate immune defense against Gram-positive bacteria. The enzyme traverses the thick peptidoglycan layer of Gram-positive bacteria to reach the phospholipid membrane where it catalyzes the hydrolysis of phosphatidylglycerol, ultimately leading to bacterial death through lysis. In comparison to other Gram-positive bacteria, Group A Streptococcus (GAS), or Streptococcus pyogenes is remarkably resistant to hGIIA activity. GAS transposon library screens, designed to identify genes that provide susceptibility/resistance to hGIIA, uncovered a number of genes involved in biosynthesis and modification of Lancefield group A carbohydrate (GAC) and lipoteichoic acid (LTA), two crucial cell envelope constituents of GAS. GAC is rhamnose-containing glycopolymer covalently attached to peptidoglycan. Modification of GAC with negatively charged glycerol phosphate as well as the absence of positively-charged D-alanine modifications in LTA drastically compromise GAS survival when challenged with hGIIA. This project seeks to identify the functions of two previously uncharacterized proteins identified by hGIIA sensitivity screen, a putative GAC hydrolase and a GT-C type membrane glycosyltransferase. Our preliminary data indicate that these proteins are involved in modifications of GAS cell envelope components: GAC and membrane phospholipids. We will define the functional roles of these two proteins using a range of genetic, biochemical, analytical and structural approaches. Functional characterization of these novel targets will lead to an increased understanding of how antimicrobial resistance is regulated in all Gram-positive bacteria and how resistance to antimicrobials is emerging among Gram-positive pathogens.
|Effective start/end date||4/6/20 → 8/31/20|
- National Institute of Allergy and Infectious Diseases: $25,583.00
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