Présentation
GLOBAL HEALTH DEPARTMENT SEMINAR
Nina van Sorge
Associate professor – Division Laboratory, Pharmacy and Biomedical Genetics
University Medical Center Utrecht, The Netherlands
“Molecular insights into host-pathogen reveals potential new therapeutic targets for MRSA and streptococci”
Jeudi 13 juin 2019 à 14h00
Auditorium Centre François Jacob
Invited by : Lhousseine Touqui (lhousseine.touqui@pasteur.fr)
Institut Pasteur – 25, 28, rue du Dr. Roux– 75724 PARIS CEDEX 15
Abstract :
Human Group IIA-Secreted Phospholipase A2 (hGIIA), a potent cationic bactericidal enzyme present in plasma and tissue fluids, is an important innate defense mechanism against Gram-positive bacteria. Gram-positive bacteria vary in their susceptibility to hGIIA, which may limit the efficacy of hGIIA in clearing invading pathogens. Insight into molecular resistance mechanisms of human pathogens provides insight into hGIIA mechanism of action and may open up new avenues for alternative treatments of bacterial infections. We focus on the activity of hGIIA against two formidable human pathogens, Staphylococcus aureus and Group A Streptococcus (GAS).
This presentation will highlight some of our recent findings in this area. First, we have identified that streptococcal cell wall glycopolymers are critical for hGIIA to exert its bactericidal effects (1). Second, our sPLA2-IIA susceptibility studies resulted in the discovery of a structural modification on the GAS rhamnose polysaccharides (2), which likely also has implications for vaccine design in this area. Finally, we identified lspA, encoding a lipoprotein signal peptidase, as a new S. aureus resistance gene against sPLA2-IIA as well as the last-resort antibiotic daptomycin. Furthermore, treatment of methicillin-resistant S. aureus (MRSA) with a LspA inhibitor sensitized bacteria to hGIIA-mediated killing. Therefore, inhibition of LspA may represent an interesting adjunct treatment strategy to sensitize MRSA to both endogenous and synthetic antibiotics.
References
- V. P. van Hensbergen et al., Streptococcal Lancefield polysaccharides are critical cell wall determinants for human Group IIA secreted phospholipase A2 to exert its bactericidal effects. PLoS Pathog 14, e1007348 (2018).
- R. J. Edgar et al., Discovery of glycerol phosphate modification on streptococcal rhamnose polysaccharides. Nat Chem Biol 15, 463-471 (2019).