A novel scaffold to fight Pseudomonas aeruginosa pyocyanin production: early steps to novel antivirulence drugs

Abstract

Aim: Although bacterial resistance is a growing concern worldwide, the development of antibacterial drugs has been steadily decreasing. One alternative to fight this issue relies on reducing the bacteria virulence without killing it. PhzS plays a pivotal role in pyocyanin production in Pseudomonas aeruginosa. Results: A total of 31 thiazolidinedione derivatives were evaluated as putative PhzS inhibitors, using thermo shift assays. Compounds that significantly shifted PhzS's Tm had their mode of inhibition (cofactor competitor) and affinity calculated by thermo shift assays as well. The most promising compound ( E)-5-(4-((4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)methoxy)benzylidene)thiazolidine-2,4-dione had their affinity confirmed by microscale thermophoresis (Kd = 18 μM). Cellular assays suggest this compound reduces pyocyanin production in vitro, but does not affect P. aeruginosa viability. Conclusion: The first inhibitor of PhzS is described.