Functional Genetic Analysis Reveals a 2-Alkyl-4-Quinolone Signaling System in the Human Pathogen Burkholderia pseudomallei and Related Bacteria

Abstract

Pseudomonas aeruginosa synthesizes diverse 2-alkyl-4(1H)-quinolones (AHQs), including the signaling molecule 2-heptyl-3-hydroxy-4(1H)-quinolone (PQS), via the pqsABCDE locus. By examining the genome databases, homologs of the pqs genes were identified in other bacteria. However, apart from P. aeruginosa, only Burkholderia pseudomallei and B. thailandensis contained a complete pqsA-E operon (termed hhqA-E). By introducing the B. pseudomallei hhqA and hhqE genes into P. aeruginosa pqsA and pqsE mutants, we show that they are functionally conserved and restore virulence factor and PQS production. B. pseudomallei, B. thailandensis, B. cenocepacia, and P. putida each produced 2-heptyl-4(1H)-quinolone (HHQ), but not PQS. Mutation of hhqA in B. pseudomallei resulted in the loss of AHQ production, altered colony morphology, and enhanced elastase production, which was reduced to parental levels by exogenous HHQ. These data reveal a role for AHQs in bacterial cell-to-cell communication beyond that seen in P. aeruginosa.

Biosensor-based assays for PQS, HHQ and related 2-alkyl-4-quinolone quorum sensing signal molecules

“…Subsequently, AHQs were discovered to inhibit the growth of Gram-positive bacteria, algae and phytoplankton, to modulate host immune defences, chelate iron and act as QS signal molecules [12][13][14][15][16][17][18] . Other pseudomonads, Burkholderia and Alteromonas species also produce AHQs and it is highly likely that other Gram-negative bacteria such as Ralstonia species synthesize these compounds as they possess homologs of the P. aeruginosa and B. pseudomallei AHQ biosynthetic genes 19 .…”

P. aeruginosa Quorum Sensing System and the Experimental Model of Chronic Respiratory Infection: Scientific Letter

“…9 The ot her system, AHQ sig nals inc lu de 2-heptyl-3-hydroxy-4-qu i no lo ne (Pse u domo nas Qu i no lo ne Sig nal, PQS) and 2-heptyl-4-qui no lo ne (HHQ). [10][11][12] PQS is synthe si zed vi a the pqs-ABC DE ope ron, which is res pon sib le for ge ne ra ting mul tip le Aqs, inc lu ding 2-heptyl-4-qu i no lo ne (HHQ), the im me di a te PQS pre cur sor. In ad di ti on, PQS sig na ling plays an im por tant ro le in P. ae ru gino sa pat ho ge ne sis be ca u se it re gu la tes the pro ducti on of di ver se vi ru len ce fac tors inc lu ding elas ta se, pyoc ya nin and Le cA lec tin, al so inf lu en ces bi o film for ma ti on.…”

Exploring the chemical space of ureidothiophene-2-carboxylic acids as inhibitors of the quorum sensing enzyme PqsD from Pseudomonas aeruginosa

“…[3] Whereas the AHL systems are widespread among Gram negative bacteria, [8] our group focuses on the so called Pseudomonas quinolone signal quorum sensing (PQS-QS) system, an AQ system that exclusively exists in P. aeruginosa and some Burkholderia strains. [9] It is involved in the production of a number of virulence factors that contribute to their pathogenicity. [10] Moreover, it takes part in regulating the formation of biofilms, a main cause for bacterial resistance against conventional antibiotics in clinical use.…”