Quinolones: from antibiotics to autoinducers
TL;DR: This work reviews 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.
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 bc1 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.
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TL;DR: This Review examines how features of quorum sensing signal–response systems combine to control collective behaviours in Gram-negative bacteria and the implications for host–microbial associations and antibacterial therapy.
Abstract: Bacteria use quorum sensing to orchestrate gene expression programmes that underlie collective behaviours. Quorum sensing relies on the production, release, detection and group-level response to extracellular signalling molecules, which are called autoinducers. Recent work has discovered new autoinducers in Gram-negative bacteria, shown how these molecules are recognized by cognate receptors, revealed new regulatory components that are embedded in canonical signalling circuits and identified novel regulatory network designs. In this Review we examine how, together, these features of quorum sensing signal-response systems combine to control collective behaviours in Gram-negative bacteria and we discuss the implications for host-microbial associations and antibacterial therapy.
1,401 citations
TL;DR: An overview of the host response and how the genomic capacity of P. aeruginosa contributes to the pathogenesis and persistence of these infections is provided.
Abstract: Pseudomonas aeruginosa is a metabolically versatile bacterium that can cause a wide range of severe opportunistic infections in patients with serious underlying medical conditions. These infections are characterized by an intense neutrophilic response resulting in significant damage to host tissues and often exhibit resistance to antibiotics leading to mortality. Treatment of persistent infections is additionally hampered by adaptive resistance, due to the growth state of the bacterium in the patient including the microorganism's ability to grow as a biofilm. An array of P. aeruginosa virulence factors counteract host defences and can cause direct damage to host tissues or increase the bacterium's competitiveness. New prevention and treatment methods are urgently required to improve the outcome of patients with P. aeruginosa infections. This review describes the two main types of P. aeruginosa lung infections and provides an overview of the host response and how the genomic capacity of P. aeruginosa contributes to the pathogenesis and persistence of these infections.
1,032 citations
Cites background from "Quinolones: from antibiotics to aut..."
...The third autoinducer is a 2-heptyl-3-hydroxy-4-quinolone designated the Pseudomonas quinolone signal, which is synthesized by a complex multistep process involving two operons, pqsABCDE and phnAB, and three genes located outside these operons, pqsR, pqsH, and pqsL (Deep et al., 2011; Heeb et al., 2011)....
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...These QS systems act in a hierarchical manner, with the las system positively regulating both rhl and the production of quinolones (Heeb et al., 2011)....
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...…autoinducer is a 2-heptyl-3-hydroxy-4-quinolone designated the Pseudomonas quinolone signal, which is synthesized by a complex multistep process involving two operons, pqsABCDE and phnAB, and three genes located outside these operons, pqsR, pqsH, and pqsL (Deep et al., 2011; Heeb et al., 2011)....
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TL;DR: Advances in bioinformatics, mass spectrometry, proteomics, transcriptomics, metabolomics and gene expression are driving the new field of microbial genome mining for applications in natural product discovery and development.
Abstract: Microorganisms have provided abundant sources of natural products which have been developed as commercial products for human medicine, animal health, and plant crop protection. In the early years of natural product discovery from microorganisms (The Golden Age), new antibiotics were found with relative ease from low-throughput fermentation and whole cell screening methods. Later, molecular genetic and medicinal chemistry approaches were applied to modify and improve the activities of important chemical scaffolds, and more sophisticated screening methods were directed at target disease states. In the 1990s, the pharmaceutical industry moved to high-throughput screening of synthetic chemical libraries against many potential therapeutic targets, including new targets identified from the human genome sequencing project, largely to the exclusion of natural products, and discovery rates dropped dramatically. Nonetheless, natural products continued to provide key scaffolds for drug development. In the current millennium, it was discovered from genome sequencing that microbes with large genomes have the capacity to produce about ten times as many secondary metabolites as was previously recognized. Indeed, the most gifted actinomycetes have the capacity to produce around 30-50 secondary metabolites. With the precipitous drop in cost for genome sequencing, it is now feasible to sequence thousands of actinomycete genomes to identify the "biosynthetic dark matter" as sources for the discovery of new and novel secondary metabolites. Advances in bioinformatics, mass spectrometry, proteomics, transcriptomics, metabolomics and gene expression are driving the new field of microbial genome mining for applications in natural product discovery and development.
664 citations
Cites background from "Quinolones: from antibiotics to aut..."
...CL3849, as well as various plant sources [50]....
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TL;DR: The synthetic isoquinoline alkaloid virstatin, for example, inhibits the transcriptional regulator ToxT in Vibrio cholerae, preventing expression of cholera toxin and fimbriae and conferring in vivo protection against intestinal colonisation.
564 citations
Cites background from "Quinolones: from antibiotics to aut..."
...[34] Heeb S, Fletcher MP, Chhabra SR, Diggle SP, Williams P, Cámara M....
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...In micro-organisms, for example, alkaloids ct as feeding deterrents [33], allelochemicals, autoinducers and iderophores [34]....
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...Naturally occurring quinolone alkaloids lack the 3-carboxyl roup that enables synthetic quinolones such as the fluorouinolones to inhibit the type II topoisomerase enzymes [34]....
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TL;DR: Quorum sensing is a widespread process in bacteria that employs autoinducing chemical signals to coordinate diverse, often cooperative activities such as bioluminescence, biofilm formation, and exoenzyme secretion and appreciating social dynamics is pertinent to understanding the efficacy of QS-inhibiting drugs and the evolution of resistance.
Abstract: Quorum sensing (QS) is a widespread process in bacteria that employs autoinducing chemical signals to coordinate diverse, often cooperative activities such as bioluminescence, biofilm formation, and exoenzyme secretion. Signaling via acyl-homoserine lactones is the paradigm for QS in Proteobacteria and is particularly well understood in the opportunistic pathogen Pseudomonas aeruginosa. Despite thirty years of mechanistic research, empirical studies have only recently addressed the benefits of QS and provided support for the traditional assumptions regarding its social nature and its role in optimizing cell-density-dependent group behaviors. QS-controlled public-goods production has served to investigate principles that explain the evolution and stability of cooperation, including kin selection, pleiotropic constraints, and metabolic prudence. With respect to medical application, appreciating social dynamics is pertinent to understanding the efficacy of QS-inhibiting drugs and the evolution of resistance....
484 citations
Cites background from "Quinolones: from antibiotics to aut..."
...Another layer of complexity is added by the Pseudomonas quinolone signal (PQS) system, which is intertwined with the AHL signaling circuitry (44)....
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References
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TL;DR: It is proposed that the size and complexity of the P. aeruginosa genome reflect an evolutionary adaptation permitting it to thrive in diverse environments and resist the effects of a variety of antimicrobial substances.
Abstract: Pseudomonas aeruginosa is a ubiquitous environmental bacterium that is one of the top three causes of opportunistic human infections. A major factor in its prominence as a pathogen is its intrinsic resistance to antibiotics and disinfectants. Here we report the complete sequence of P. aeruginosa strain PAO1. At 6.3 million base pairs, this is the largest bacterial genome sequenced, and the sequence provides insights into the basis of the versatility and intrinsic drug resistance of P. aeruginosa. Consistent with its larger genome size and environmental adaptability, P. aeruginosa contains the highest proportion of regulatory genes observed for a bacterial genome and a large number of genes involved in the catabolism, transport and efflux of organic compounds as well as four potential chemotaxis systems. We propose that the size and complexity of the P. aeruginosa genome reflect an evolutionary adaptation permitting it to thrive in diverse environments and resist the effects of a variety of antimicrobial substances.
4,220 citations
"Quinolones: from antibiotics to aut..." refers background in this paper
...For instance, P. aeruginosa encodes at least 12 RND systems (Stover et al., 2000; Schweizer, 2003), eight of which (MexAB-OprM, MexCD-OprJ, MexEF-OprN, MexXYOprM, MexJK-OprM, MexHI-OpmD, MexVW-OprM and MexPQ-OpmE) have been reported to export fluoroquinolones and other antibiotics (Chuanchuen et…...
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TL;DR: Network motifs are reviewed, suggesting that they serve as basic building blocks of transcription networks, including signalling and neuronal networks, in diverse organisms from bacteria to humans.
Abstract: Transcription regulation networks control the expression of genes. The transcription networks of well-studied microorganisms appear to be made up of a small set of recurring regulation patterns, called network motifs. The same network motifs have recently been found in diverse organisms from bacteria to humans, suggesting that they serve as basic building blocks of transcription networks. Here I review network motifs and their functions, with an emphasis on experimental studies. Network motifs in other biological networks are also mentioned, including signalling and neuronal networks.
3,076 citations
"Quinolones: from antibiotics to aut..." refers background in this paper
...…QS systems are linked to AQ production and regulation, forming an incoherent feed-forward loop likely to produce accelerated pulse-like responses (Alon, 2007): the las system positively controls AQ production by inducing the pqsR and pqsA promoters and the rhl system downregulates its effects…...
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...Therefore, it appears that PtxR could be part of an intricate network of feed-forward loops (Alon, 2007) that connect the las, rhl and pqs QS systems....
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TL;DR: Surprisingly, despite little or no sequence homology, both type IA and type IIA topoisomerases from prokaryotes and the typeIIA enzymes from eukaryotes share structural folds that appear to reflect functional motifs within critical regions of the enzymes.
Abstract: ▪ Abstract DNA topoisomerases solve the topological problems associated with DNA replication, transcription, recombination, and chromatin remodeling by introducing temporary single- or double-strand breaks in the DNA. In addition, these enzymes fine-tune the steady-state level of DNA supercoiling both to facilitate protein interactions with the DNA and to prevent excessive supercoiling that is deleterious. In recent years, the crystal structures of a number of topoisomerase fragments, representing nearly all the known classes of enzymes, have been solved. These structures provide remarkable insights into the mechanisms of these enzymes and complement previous conclusions based on biochemical analyses. Surprisingly, despite little or no sequence homology, both type IA and type IIA topoisomerases from prokaryotes and the type IIA enzymes from eukaryotes share structural folds that appear to reflect functional motifs within critical regions of the enzymes. The type IB enzymes are structurally distinct from a...
2,513 citations
Additional excerpts
...All rights reserved (Champoux, 2001; Wang, 2002; Corbett & Berger, 2004; Leo et al., 2005; Drlica et al., 2009)....
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TL;DR: In this review, the cellular roles of these enzymes are examined from a molecular point of view.
Abstract: DNA topoisomerases are the magicians of the DNA world — by allowing DNA strands or double helices to pass through each other, they can solve all of the topological problems of DNA in replication, transcription and other cellular transactions. Extensive biochemical and structural studies over the past three decades have provided molecular models of how the various subfamilies of DNA topoisomerase manipulate DNA. In this review, the cellular roles of these enzymes are examined from a molecular point of view.
2,194 citations
Additional excerpts
...All rights reserved (Champoux, 2001; Wang, 2002; Corbett & Berger, 2004; Leo et al., 2005; Drlica et al., 2009)....
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TL;DR: Bacterial biofilms are structured communities of cells enclosed in self-produced hydrated polymeric matrix adherent to an inert or living surface that have inherent resistance to antibiotics and host immune attack.
Abstract: Bacterial biofilms are structured communities of cells enclosed in self-produced hydrated polymeric matrix adherent to an inert or living surface ([1][1]). Formation of these sessile communities and their inherent resistance to antibiotics and host immune attack are at the root of many persistent
1,962 citations
"Quinolones: from antibiotics to aut..." refers background in this paper
...Pseudomonas aeruginosa can also release, possibly through lysis of cell subpopulations, extracellular DNA, which acts as an interconnecting matrix in bacterial biofilms (Whitchurch et al., 2002)....
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