Quinolones: from antibiotics to autoinducers

Abstract

Since quinine was first isolated, animals, plants and microorganisms producing a wide variety of quinolone compounds have been discovered, several of which possess medicinally interesting properties ranging from antiallergenic and anticancer to antimicrobial activities. Over the years, these have served in the development of many synthetic drugs, including the successful fluoroquinolone antibiotics. Pseudomonas aeruginosa and related bacteria produce a number of 2-alkyl-4(1H)-quinolones, some of which exhibit antimicrobial activity. However, quinolones such as the Pseudomonas quinolone signal and 2-heptyl-4-hydroxyquinoline act as quorum-sensing signal molecules, controlling the expression of many virulence genes as a function of cell population density. Here, we review selectively this extensive family of bicyclic compounds, from natural and synthetic antimicrobials to signalling molecules, with a special emphasis on the biology of P. aeruginosa. In particular, we review their nomenclature and biochemistry, their multiple properties as membrane-interacting compounds, inhibitors of the cytochrome bc(1) complex and iron chelators, as well as the regulation of their biosynthesis and their integration into the intricate quorum-sensing regulatory networks governing virulence and secondary metabolite gene expression.

Fig. 1

Natural and synthetic quinolones of medicinal interest, quinolone antibiotics. Several plant, animal and microbial species produce quinolone compounds of medicinal interest such as the antimalarial quinine extracted from Cinchona spp., or the 2-quinolone casimiroine, an antimutagen extracted from Casimiroa edulis. Among the synthetic 2-quinolones are the antiulcer agent rebamipide and the antihistamine, repirinast. Naturally occurring quinolones having antimicrobial activities such as evocarpine and related compounds (nos 1–17) produced by Evodia rutaecarpa are active against Helicobacter pylori, a causative agent of peptic ulcers and gastric cancer. The quest for synthetic analogues of quinine led to the discovery of nalidixic acid, oxolinic acid and cinoxacin, and then to the development of an extensive family of fluoroquinolone antibiotics such as flumequine, norfloxacin and ciprofloxacin. The heteroaromatic ring atom numbering common to all quinolones is indicated for quinine.

Fig. 2

Structure, IUPAC names and abbreviations of AQ molecules synthesized by Pseudomonas aeruginosa and a synthetic analogue. Both the tautomeric lactam and the phenolic forms of each molecule are shown. Arrows indicate the equilibrium of these molecules as would exist under physiological conditions. Where more than one name exists for a molecule, the IUPAC designation is indicated, although this may not be the nomenclature used most frequently. The compound C1-PQS is a synthetic analogue that is not produced by P. aeruginosa.

Fig. 3

Sulphur-containing quinolones produced by some pseudomonads. Thioquinolobactin, a compound exhibiting strong antifungal properties, is produced by P. fluorescens ATCC 17400. Upon spontaneous hydrolysis, thioquinolobactin is rapidly converted into quinolobactin, which then acts as a siderophore. Pseudomonas fluorescens G308 produces Cbs, which also exhibits potent fungicidal properties.

Fig. 4

Proposed biosynthetic pathway of PQS, HHQ, HQNO and DHQ in Pseudomonas aeruginosa. AQs are derived from a condensation reaction between anthranilate and β-keto fatty acids. Anthranilate is derived from either the PhnAB/TrpEG or the KynABU metabolic pathways using either chorismate or tryptophan as precursors, respectively. Anthranilate is first activated with coenzyme A (CoA) by PqsA. Anthranilate-CoA and an activated β-ketodecanoate are condensed, possibly via the PqsBCD enzymes to HHQ, releasing CO₂ and H₂O. The monooxygenase PqsH converts HHQ to PQS. HQNO is derived from the same starting products as HHQ, but utilizes the additional monooxygenase PqsL. HHQ is not a precursor for HQNO. DHQ, which technically is not an AQ, is produced by PqsD independent of PqsB and PqsC.

Fig. 5

Regulation of AQ production inPseudomonas aeruginosa. The las QS system positively regulates the transcription of pqsR, pqsABCDE and pqsH. The PqsABCD proteins synthesize HHQ, which is converted to PQS by PqsH. Autoinduction occurs when either HHQ or PQS binds to PqsR and enhances the expression of the pqs operon. The rhl QS system, also positively controlled by the las system, exerts a negative effect on the AQ system, although it is itself positively regulated by AQs. The terminal output of this regulatory network is the PqsE protein of still unknown enzymatic function. In addition, PQS, via an unknown mechanism, positively controls the transcription of the small RNA RsmZ, which in turns has a negative effect on the RNA-binding protein RsmA involved in post-transcriptional regulation. Biosynthetic enzymes are represented by globular shapes, while transcriptional regulators are shown as cubes. Filled arrows and blunted lines represent positive and negative regulation, respectively.