The end of an old hypothesis: the pseudomonas signaling molecules 4-hydroxy-2-alkylquinolines derive from fatty acids, not 3-ketofatty acids.
Groups of pathogenic bacteria use diffusible signals to regulate their virulence in a concerted manner. Pseudomonas aeruginosa uses 4-hydroxy-2-alkylquinolines (HAQs), including 4-hydroxy-2-heptylquinoline (HHQ) and 3,4-dihydroxy-2-heptylquinoline (PQS), as unique signals. We demonstrate that octanoic acid is directly incorporated into HHQ. This finding rules out the long-standing hypothesis that 3-ketofatty acids are the precursors of HAQs. We found that HAQ biosynthesis, which requires the PqsABCD enzymes, proceeds by a two-step pathway: (1) PqsD mediates the synthesis of 2-aminobenzoylacetate (2-ABA) from anthraniloyl-coenzyme A (CoA) and malonyl-CoA, then (2) the decarboxylating coupling of 2-ABA to an octanoate group linked to PqsC produces HHQ, the direct precursor of PQS. PqsB is tightly associated with PqsC and required for the second step. This finding uncovers promising targets for the development of specific antivirulence drugs to combat this opportunistic pathogen.
INRS-Institut Armand-Frappier, Université du Québec, 531 Boulevard des Prairies, Laval, QC H7V 1B7, Canada.
Carlos Eduardo
CE
Dulcey
INRS-Institut Armand-Frappier, Université du Québec, 531 Boulevard des Prairies, Laval, QC H7V 1B7, Canada.
Valérie
V
Dekimpe
INRS-Institut Armand-Frappier, Université du Québec, 531 Boulevard des Prairies, Laval, QC H7V 1B7, Canada.
David-Alexandre
DA
Fauvelle
INRS-Institut Armand-Frappier, Université du Québec, 531 Boulevard des Prairies, Laval, QC H7V 1B7, Canada.
Sylvain
S
Milot
INRS-Institut Armand-Frappier, Université du Québec, 531 Boulevard des Prairies, Laval, QC H7V 1B7, Canada.
Marie-Christine
MC
Groleau
INRS-Institut Armand-Frappier, Université du Québec, 531 Boulevard des Prairies, Laval, QC H7V 1B7, Canada.
Nicolas
N
Doucet
Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 50 Blossom Street, Boston, MA 02114, USA.
Laurence G
LG
Rahme
INRS-Institut Armand-Frappier, Université du Québec, 531 Boulevard des Prairies, Laval, QC H7V 1B7, Canada. Electronic address: francois.lepine@iaf.inrs.ca.
François
F
Lépine
INRS-Institut Armand-Frappier, Université du Québec, 531 Boulevard des Prairies, Laval, QC H7V 1B7, Canada. Electronic address: eric.deziel@iaf.inrs.ca.
Eric
E
Déziel
D053898:Biosynthetic Pathways; D005227:Fatty Acids / Q000378:metabolism*; D011550:Pseudomonas aeruginosa / Q000201:enzymology* / Q000378:metabolism*; D011804:Quinolines / Q000378:metabolism*
D005227:Fatty Acids; D011804:Quinolines