Obiettivo Staphylococcus aureus infections are associated with significant morbidity and mortality in healthcare and community settings. Inside the host, invading S. aureus is challenged by host innate immune defenses that include professional phagocytes and an arsenal of secreted antimicrobials. Long term persistence of S. aureus may be due to adoption of quiescent physical and metabolic states, such as biofilms, endocardial vegetations, and small colony variants. The metabolic changes needed for adaptation and long term survival inside the host are largely unknown. Our preliminary studies have revealed a pronounced metabolic switch that results in a change of the membrane composition from the major phospholipid phosphatidylglycerol (PG) to cardiolipin (CL). This striking lipid change occurs when S. aureus is phagocytosed by neutrophils and can also be mimicked in vitro in the stationary phase of growth, or through ATP depletion. Our central hypothesis is that adaptive lipid changes are essential for optimal survival of S. aureus under adverse conditions. In bacteria, CL is mainly synthesized by membrane-bound cardiolipin synthase enzymes (CLS). The S. aureus genome contains two open reading frames putatively encoding CLS, each with ~30% identity to the E. coli CLS enzymes. The function of the two S. aureus CLSs have not been explored and will be the focus of this grant proposal. Towards this end, we will investigate the: (i) function of CLS enzyme 1 and enzyme 2 in lipid metabolism, (II) role of CL in lipoteichoic acid generation, (III) requirement for CL during in vitro persistence and survival in planktonic cultures, in (IV) endocardial vegetations, and (V) interactions with host defenses. Understanding of the molecular mechanisms and regulation of CL synthesis in S. aureus may uncover novel targets for the development of anti-Staphylococcal agents. Campo scientifico social sciencessociologydemographymortalitynatural sciencesbiological sciencesmicrobiologybacteriologynatural sciencesbiological sciencesbiochemistrybiomoleculeslipidsnatural sciencesbiological sciencesgeneticsgenomesnatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymes Programma(i) FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Argomento(i) FP7-PEOPLE-2009-RG - Marie Curie Action: "Reintegration Grants" Invito a presentare proposte FP7-PEOPLE-2009-RG Vedi altri progetti per questo bando Meccanismo di finanziamento MC-IRG - International Re-integration Grants (IRG) Coordinatore KEMIJSKI INSTITUT Contributo UE € 100 000,00 Indirizzo HAJDRIHOVA 19 1000 Ljubljana Slovenia Mostra sulla mappa Regione Slovenija Zahodna Slovenija Osrednjeslovenska Tipo di attività Research Organisations Contatto amministrativo Roman Jerala (Dr.) Collegamenti Contatta l’organizzazione Opens in new window Sito web Opens in new window Costo totale Nessun dato