Controlling the virulence of Pseudomonas aeruginosa through inhibiting the synthesis of pyoverdine

Pseudomonas aeruginosa still becomes a bacteria of concern to be investigated due to its resistance to several antibiotics. Many efforts have been done to find a novel drug against the infections caused by P. aeruginosa. Recently, the iron uptake mechanism facilitated by siderophores attracts the attention to be explored as a novel target to find a new treatment against the infections. The biosynthesis of pyoverdine (a major siderophore) involves many enzymes where these enzymes could potentially be exploited as drug targets. In this thesis, Joko Priyanto Wibowo demonstrates that the iron uptake mechanism can be exploited to be a novel target to develop new treatments against P. aeruginosa infections by inhibiting PvdP and PvdQ, both are responsible for the biosynthesis of pyoverdine. The PvdP knock-out mutant demonstrated the importance of the enzyme in the virulence of P. aeruginosa. The solvation of the crystal structure of PvdP especially the one that binds to the inhibitor leads to the development of a novel and highly potent inhibitor of PvdP. In addition, the finding of a new inhibitor of PvdQ also opens more alternative ways to obtain new treatments against Pseudomonas infections. The application of PvdP and PvdQ inhibitor in the Galleria mellonella infection model successfully interferes with the iron uptake into the bacterial cell, as a result, reducing the virulence of P. aeruginosa in vivo.