Fighting pathogens by targeting a molecular chaperone responsible for stress adaptation – PseudoChap

Multidrug-resistant bacteria represent a major public health problem and it is becoming essential to develop new strategies to fight them. A prerequisite is to better understand how pathogens adapt and resist to stresses during infection. Surprisingly, the role of chaperones, major players in protein folding and stability during stress, has been little investigated in this context. However, our preliminary results suggest that one of these chaperones, Hsp90, could be key for the virulence of Pseudomonas aeruginosa, an opportunistic pathogen of humans classified by the WHO in the top 3 most critical bacteria for antibiotic resistance. Indeed, we have shown that Hsp90 in P. aeruginosa is required for the biosynthesis of a major virulence factor, the pyoverdine siderophore, and Hsp90 participates in biofilm formation.
The goal of our project is to define at the molecular level the role of Hsp90 in the physiology and virulence of P. aeruginosa. Three work packages are designed to (i) determine how Hsp90 promotes pyoverdine biosynthesis, (ii) reveal the involvement of Hsp90 in other pathogeninicty mechanisms including biofilm formation, and (iii) measure the contribution of Hsp90 to P. aeruginosa virulence in model animals and test the impact of Hsp90 inhibitors.
Our results could define Hsp90 as a target of choice for the development of new anti-virulence strategies to disarm pathogenic bacteria, a promising alternative to the use of antibiotics. This project involves 4 partners specialized in chaperone proteins, bacterial virulence factors and siderophore biosynthesis with complementary expertise in molecular microbiology, bacterial pathogenicity, biochemistry, and in vivo models.