Dioxygenase-Mediated Quenching of Quinolone-Dependent Quorum Sensing in Pseudomonas aeruginosa

Pustelny, Christian; Albers, Alexander; Büldt-Karentzopoulos, Klaudia; Parschat, Katja; Chhabra, Siri Ram; Cámara, Miguel; Williams, Paul; Fetzner, Susanne

doi:10.1016/j.chembiol.2009.11.013

Cited by 103 publications

(89 citation statements)

References 60 publications

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“…degrade the Pseudomonas quinolone signal (PQS), 2-heptyl-3-hydroxy-4(1H)-quinolone, to acylated anthranilic acids (28). Given that B. thailandensis does not encode a hod with significant homology to that of Arthrobacter, we prefer the former explanation.…”

Section: Resultsmentioning

confidence: 88%

Discovery of scmR as a global regulator of secondary metabolism and virulence in Burkholderia thailandensis E264

Mao

Bushin

Moon

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

140

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Bacteria produce a diverse array of secondary metabolites that have been invaluable in the clinic and in research. These metabolites are synthesized by dedicated biosynthetic gene clusters (BGCs), which assemble architecturally complex molecules from simple building blocks. The majority of BGCs in a given bacterium are not expressed under normal laboratory growth conditions, and our understanding of how they are silenced is in its infancy. Here, we have addressed this question in the Gram-negative model bacterium Burkholderia thailandensis E264 using genetic, transcriptomic, metabolomic, and chemical approaches. We report that a previously unknown, quorum-sensing-controlled LysR-type transcriptional regulator, which we name ScmR (for secondary metabolite regulator), serves as a global gatekeeper of secondary metabolism and a repressor of numerous BGCs. Transcriptionally, we find that 13 of the 20 BGCs in B. thailandensis are significantly (threefold or more) upor down-regulated in a scmR deletion mutant (ΔscmR). Metabolically, the ΔscmR strain displays a hyperactive phenotype relative to wild type and overproduces a number of compound families by 18-to 210-fold, including the silent virulence factor malleilactone. Accordingly, the ΔscmR mutant is hypervirulent both in vitro and in a Caenorhabditis elegans model in vivo. Aside from secondary metabolism, ScmR also represses biofilm formation and transcriptionally activates ATP synthesis and stress response. Collectively, our data suggest that ScmR is a pleiotropic regulator of secondary metabolism, virulence, biofilm formation, and other stationary phase processes. A model for how the interplay of ScmR with pathwayspecific transcriptional regulators coordinately silences virulence factor production is proposed.biosynthetic gene clusters | natural products | Burkholderia thailandensis | regulation | virulence

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Section: Resultsmentioning

confidence: 88%

Discovery of scmR as a global regulator of secondary metabolism and virulence in Burkholderia thailandensis E264

Mao

Bushin

Moon

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

140

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“…Synthetic anthranilate derivatives (23,36,116) have been developed and have shown promising results in a P. aeruginosa mouse infection model (116). In parallel, Fetzner and coworkers reported PQS-degrading activity by conversion of PQS to N-octanoylanthranilic acid by the dioxygenase Hod (1H-3-hydroxy-4-oxoquinaldine 2,4-dioxygenase) of Arthrobacter nitroguajacolicus (162). Hod and the Pseudomonas putida homologue QDO (1H-3-hydroxy-4-oxoquinoline 2,4-dioxygenase) (8) belong to an unusual family of cofactor-independent dioxygenases involved in the breakdown of N-heteroaromatic compounds (187).…”

Section: Targeting Bacterial Signalingmentioning

confidence: 93%

The Multiple Signaling Systems Regulating Virulence in Pseudomonas aeruginosa

Nadal‐Jimenez

Koch

Thompson

et al. 2012

Microbiol Mol Biol Rev

629

626

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SUMMARY Cell-to-cell communication is a major process that allows bacteria to sense and coordinately react to the fluctuating conditions of the surrounding environment. In several pathogens, this process triggers the production of virulence factors and/or a switch in bacterial lifestyle that is a major determining factor in the outcome and severity of the infection. Understanding how bacteria control these signaling systems is crucial to the development of novel antimicrobial agents capable of reducing virulence while allowing the immune system of the host to clear bacterial infection, an approach likely to reduce the selective pressures for development of resistance. We provide here an up-to-date overview of the molecular basis and physiological implications of cell-to-cell signaling systems in Gram-negative bacteria, focusing on the well-studied bacterium Pseudomonas aeruginosa . All of the known cell-to-cell signaling systems in this bacterium are described, from the most-studied systems, i.e., N -acyl homoserine lactones (AHLs), the 4-quinolones, the global activator of antibiotic and cyanide synthesis (GAC), the cyclic di-GMP (c-di-GMP) and cyclic AMP (cAMP) systems, and the alarmones guanosine tetraphosphate (ppGpp) and guanosine pentaphosphate (pppGpp), to less-well-studied signaling molecules, including diketopiperazines, fatty acids (diffusible signal factor [DSF]-like factors), pyoverdine, and pyocyanin. This overview clearly illustrates that bacterial communication is far more complex than initially thought and delivers a clear distinction between signals that are quorum sensing dependent and those relying on alternative factors for their production.

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“…Experiments using purified Hod enzyme demonstrated enzyme-mediated inhibition of PQS signaling in cultures of P. aeruginosa, but Hod progressively lost activity during incubation in spent culture supernatants due to proteolytic degradation by secreted bacterial proteases. Using a lettuce leaf model of P. aeruginosa infection, Pustelny et al were also able to demonstrate that loss of PQS, by either deletion of pqsA or coinjection of Hod enzyme, resulted in attenuation of virulence in planta (83).…”

Section: Enzymatic Inactivation Of Non-ahl Qs Signalsmentioning

confidence: 99%

“…2) and 3-hydroxy-2-methyl-4(1H)-quinolone (MPQS), an intermediate of the quinaldine utilization pathway in Arthrobacter nitroguajacolicus, by the labs of Williams and Fetzner led to the postulation that the deoxygenase responsible for cleavage of MPQS, Hod, would also recognize PQS as a substrate (83). Experiments confirmed this hypothesis to be correct; Hodmediated degradation of PQS produced N-octanoylanthranilic acid and carbon monoxide, presumably resulting from 2,4-dioxygenolytic ring cleavage (83). Experiments using purified Hod enzyme demonstrated enzyme-mediated inhibition of PQS signaling in cultures of P. aeruginosa, but Hod progressively lost activity during incubation in spent culture supernatants due to proteolytic degradation by secreted bacterial proteases.…”

Section: Enzymatic Inactivation Of Non-ahl Qs Signalsmentioning

confidence: 99%

Exploiting Quorum Sensing To Confuse Bacterial Pathogens

LaSarre

Federle

2013

Microbiol Mol Biol Rev

678

556

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SUMMARY Cell-cell communication, or quorum sensing, is a widespread phenomenon in bacteria that is used to coordinate gene expression among local populations. Its use by bacterial pathogens to regulate genes that promote invasion, defense, and spread has been particularly well documented. With the ongoing emergence of antibiotic-resistant pathogens, there is a current need for development of alternative therapeutic strategies. An antivirulence approach by which quorum sensing is impeded has caught on as a viable means to manipulate bacterial processes, especially pathogenic traits that are harmful to human and animal health and agricultural productivity. The identification and development of chemical compounds and enzymes that facilitate quorum-sensing inhibition (QSI) by targeting signaling molecules, signal biogenesis, or signal detection are reviewed here. Overall, the evidence suggests that QSI therapy may be efficacious against some, but not necessarily all, bacterial pathogens, and several failures and ongoing concerns that may steer future studies in productive directions are discussed. Nevertheless, various QSI successes have rightfully perpetuated excitement surrounding new potential therapies, and this review highlights promising QSI leads in disrupting pathogenesis in both plants and animals.

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Dioxygenase-Mediated Quenching of Quinolone-Dependent Quorum Sensing in Pseudomonas aeruginosa

Cited by 103 publications

References 60 publications

Discovery of scmR as a global regulator of secondary metabolism and virulence in Burkholderia thailandensis E264

Discovery of scmR as a global regulator of secondary metabolism and virulence in Burkholderia thailandensis E264

The Multiple Signaling Systems Regulating Virulence in Pseudomonas aeruginosa

Exploiting Quorum Sensing To Confuse Bacterial Pathogens

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