Synthesis of PQS and HHQ Probes for Photoaffinity Labeling

Rambabu Dandela, Chemistry, Ben-Gurion University of the Negev, Beer-Sheva, Israel
Josep Rayo, Chemistry, Ben-Gurion University of the Negev, Beer-Sheva, Israel
Michael M. Meijler, Chemistry, Ben-Gurion University of the Negev, Beer-Sheva, Israel

Pseudomonas aeruginosa is the most common Gram-negative bacterium found in nosocomial infections. It primarily infects immunocompromised individuals and cystic fibrosis patients. Among the key compounds involved in the regulation of virulence factor production of these bacteria are quinolones, such as 2-heptyl-3-hydroxy-4(1H)-quinolone (PQS) and its direct precursor 2-heptyl-4(1H)-quinolone (HHQ).  Development of antagonists or inhibitors for these kind of compounds form a promising strategy to control the pathogenicity of these bacteria. We have developed an efficient synthesis that allows access to PQS and HHQ photoaffinity probes from readily available starting materials. The probes contain a photoreactive group, a diazirine moiety, and a handle which will allow us to perform biorthogonal chemistry in order to pull down potential proteins that kind the bioactive quinolones. These studies will further enhance our understanding of PQS-mediated quorum sensing systems, they will enable the development of methods that can modulate these signalling networks effectively, with possible therapeutic applications in the treatment of human bacterial infections.