A new look at the biosynthesis of 4-hydroxy-2-alkylquinolines in Pseudomonas aeruginosa

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This research program is aimed at deciphering the biosynthesis of 4-hydroxy-2-alkylquinolines (HAQs), which are a class of compounds that are involved in "Quorum Sensing", a mode of communication between bacteria. HAQs are produced by Pseudomonas aeruginosa, an opportunistic pathogen that uses Quorum Sensing to control the expression of virulence factors. Inhibiting the production of HAQs in this bacterium leads to a considerable decrease of its virulence. However, the biosynthesis of HAQs is not fully elucidated and in order to efficiently counter the production of these signaling compounds, it is important to find the role of the enzymes and intermediates involved in their biosynthesis. Although we know that the genes from the pqsABCDE operon are required for HAQ synthesis, the role of the enzymes that they encode is only partially known. Since the discovery of HAQs in the mid 1950s, it was believed that 3-ketofatty acids are intermediates in the biosynthesis of HAQs. In preliminary experiments, we discovered that instead of 3-ketofatty acids, fatty acids were the intermediates involved. This paradigm change brings new light on the role of some of the enzymes implicated in this biosynthesis pathway. Thus we now think that HAQ biosynthesis is a two-step process in which PqsD is responsible for the coupling of anthranilic acid with a malonate derivative to produce 2-amino-benzoylacetic acid and that this intermediate reacts with a fatty acid to produce HAQs. We will confirm this hypothesis by purifying the enzymes PqsB and PqsC that we hypothesize are involved in this second step. We also previously found a series of compounds that seem to inhibit specifically PqsC and/or PqsB. Once the specific role these two enzymes will be understood, we will study their inhibition by these compounds. We will look for analogs of these compounds that might be more active than those we already have. Our long-term goal is to develop a new way to inhibit infections by P. aeruginosa by targeting their quorum sensing, which would be an alternative to the use of antibiotics, an approach which leads to the development of resistance.