Fraunhofer Institute for Toxicology and Experimental Medicine
Multidrug-resistant bacteria such as Pseudomonas aeruginosa are a major cause of healthcare-associated infections, with high mortality especially in immunocompromised individuals. Despite this, the drug development pipeline is alarmingly short of suitable candidates. Successfully developing new strategies to combat P. aeruginosa infections requires a deep understanding of the factors driving the virulence and pathogenicity of these bacteria.
P. aeruginosa uridine diphosphate-glucose pyrophosphorylase (PaUGP) has been proposed as a novel drug target, as it is required for the biosynthesis of several virulence factors. As part of iCAIR® - an international research consortium dedicated to developing new anti-infective therapies - Sven Cleeves investigated the role of PaUGP as a potential drug target during his PhD at Fraunhofer ITEM. He used a UGP-deficient P. aeruginosa strain (galU-) to infect human cells and precision-cut lung slices (PCLS), and to analyze its virulence in comparison to the wildtype strain.
Infection with galU- resulted in substantially reduced cytotoxicity, while bacterial growth and colonization of cells and PCLS remained unchanged. The galU- strain further displayed reduced levels of pyocyanin, an important virulence factor, as well as impaired swarming motility - a coordinated, collective movement crucial for bacterial virulence.
These findings demonstrated the importance of PaUGP as a key virulence factor in relevant human lung models, emphasizing its potential as a novel drug target.
