Short-chain reactive probes as tools to unravel thePseudomonas aeruginosaquorum sensing regulon

In recent years, the world has seen a troubling increase in antibiotic resistance among bacterial pathogens. In order to provide alternative strategies to combat bacterial infections, it is crucial deepen our understanding into the mechanisms that pathogens use to thrive in complex environments. Most bacteria use sophisticated chemical communication systems to sense their population density and coordinate gene expression in a collective manner, a process that is termed “quorum sensing” (QS). The human pathogenPseudomonas aeruginosauses several small molecules to regulate QS, and one of them isN-butyryl-l-homoserine lactone (C₄-HSL). Using an activity-based protein profiling (ABPP) strategy, we designed biomimetic probes with a photoreactive group and a ‘click’ tag as an analytical handle. Using these probes, we have identified previously uncharacterized proteins that are part of theP. aeruginosaQS network, and we uncovered an additional role for this natural autoinducer in the virulence regulon ofP. aeruginosa, through its interaction with PhzB1/2 that results in inhibition of pyocyanin production.