PR001799 (Project)

Description:Multidrug-resistant bacteria present a major threat to public health. Therefore, new drugs or approaches are urgently needed to manage and mitigate this threat. Here, we screen the molecular candidates that allow the survival of mice upon multidrug-resistant Vibrio parahaemolyticus infection by integrated proteomic and metabolomics analysis, where L-Alanine metabolism and phagocytosis are highly correlated. The role of L-Alanine on boosting mouse survival is further confirmed with in vivo bacterial challenge studies on multidrug-resistant bacteria including V. parahaemolyticus, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae. Functional studies demonstrate that exogenous L-Alanine promotes phagocytosis to these different species of multidrug-resistant pathogens. The underlying mechanism involves two events that are L-Alanine-dependently increased TLR4 expression, and L-Alanine-enhanced TLR4 signaling via increasing the biosynthesis and secretion of fatty acids such as palmitate. Palmitate enhances the binding of LPS to TLR4 and thereby promotes TLR4 dimmer formation and endocytosis for the subsequent activation of PI3K/Akt and NF-?B pathways and phagocytosis of bacteria. These results suggest that modulation of metabolic environment is a plausible approach for combating infection with multidrug-resistant bacteria.