Design, Synthesis, and Evaluation of Transition-State Analogs as Inhibitors of the Bacterial Quorum Sensing Autoinducer Synthase CepI

Quorum sensing is a bacterial signaling system that involves the synthesis and detection of small signal molecules called autoinducers. A main class of autoinducers in Gram-negative bacteria are acylated homoserine lactones, produced by the LuxI family of autoinducer synthase enzymes and detected by the LuxR family of autoinducer receptors. Quorum sensing allows for changes in gene expression and bacterial behaviors in a coordinated, cell density dependent manner. Quorum sensing controls the expression of virulence factors in some human pathogens, making quorum sensing an antibacterial drug target. Here we describe the design and synthesis of transition-state analogs of the autoinducer synthase enzymatic reaction and evaluation of these compounds as inhibitors of the synthase CepI. One such compound potently inhibits CepI and constitutes a new type of inhibitor against this underdeveloped antibacterial target.

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Design, Synthesis, and Evaluation of Transition-State Analogs as Inhibitors of the Bacterial Quorum Sensing Autoinducer Synthase CepI

10.26434/chemrxiv.13217774.v2 ◽

2020 ◽

Author(s):

Erin Higgins ◽

Julian Kellner-Rogers ◽

Alexandra Estanislau ◽

Alec Esposito ◽

Nora R. Vail ◽

...

Keyword(s):

Quorum Sensing ◽

Transition State ◽

Enzymatic Reaction ◽

Signal Molecules ◽

Antibacterial Drug ◽

Dependent Manner ◽

Human Pathogens ◽

Design Synthesis ◽

Design And Synthesis ◽

Transition State Analogs

Quorum sensing is a bacterial signaling system that involves the synthesis and detection of small signal molecules called autoinducers. A main class of autoinducers in Gram-negative bacteria are acylated homoserine lactones, produced by the LuxI family of autoinducer synthase enzymes and detected by the LuxR family of autoinducer receptors. Quorum sensing allows for changes in gene expression and bacterial behaviors in a coordinated, cell density dependent manner. Quorum sensing controls the expression of virulence factors in some human pathogens, making quorum sensing an antibacterial drug target. Here we describe the design and synthesis of transition-state analogs of the autoinducer synthase enzymatic reaction and evaluation of these compounds as inhibitors of the synthase CepI. One such compound potently inhibits CepI and constitutes a new type of inhibitor against this underdeveloped antibacterial target.

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Design, synthesis, and evaluation of transition-state analogs as inhibitors of the bacterial quorum sensing autoinducer synthase CepI

Bioorganic & Medicinal Chemistry Letters ◽

10.1016/j.bmcl.2021.127873 ◽

2021 ◽

pp. 127873

Author(s):

Erin L. Higgins ◽

Julian S. Kellner-Rogers ◽

Alexandra M. Estanislau ◽

Alec C. Esposito ◽

Nora R. Vail ◽

...

Keyword(s):

Quorum Sensing ◽

Transition State ◽

Design Synthesis ◽

Transition State Analogs ◽

Bacterial Quorum Sensing ◽

Bacterial Quorum

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Design and Synthesis of a Triazole‐based Small Molecule Library for the Inhibition of Bacterial Quorum Sensing

The FASEB Journal ◽

10.1096/fasebj.2018.32.1_supplement.656.12 ◽

2018 ◽

Vol 32 (S1) ◽

Author(s):

Catherine E. Kruszynski ◽

Kallie Hinspeter ◽

Amy M. Danowitz

Keyword(s):

Quorum Sensing ◽

Small Molecule ◽

Design And Synthesis ◽

Small Molecule Library ◽

Bacterial Quorum Sensing ◽

Bacterial Quorum

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The Impact of Bacterial Quorum Sensing Signal Molecules on Animal Hosts: Paradigms and Perspectives

ACS Symposium Series - Quorum Sensing: Microbial Rules of Life ◽

10.1021/bk-2020-1374.ch015 ◽

2020 ◽

pp. 277-289

Author(s):

Ramakrishnan Sitaraman

Keyword(s):

Quorum Sensing ◽

Signal Molecules ◽

Bacterial Quorum Sensing ◽

Animal Hosts ◽

Bacterial Quorum ◽

The Impact

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Design, synthesis and activity evaluation study of novel substituted N-sulfonyl homoserine lactone derivatives as bacterial quorum sensing inhibitors

Medicinal Chemistry Research ◽

10.1007/s00044-017-2027-2 ◽

2017 ◽

Vol 26 (12) ◽

pp. 3345-3353 ◽

Cited By ~ 2

Author(s):

Qi Sun ◽

Mingming Zhao ◽

Jingwei Liang ◽

Junhai Xiao ◽

Fanhao Meng

Keyword(s):

Quorum Sensing ◽

Homoserine Lactone ◽

Evaluation Study ◽

Design Synthesis ◽

Activity Evaluation ◽

Quorum Sensing Inhibitors ◽

Bacterial Quorum Sensing ◽

Bacterial Quorum

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l-Canavanine Made by Medicago sativa Interferes with Quorum Sensing in Sinorhizobium meliloti

Journal of Bacteriology ◽

10.1128/jb.187.24.8427-8436.2005 ◽

2005 ◽

Vol 187 (24) ◽

pp. 8427-8436 ◽

Cited By ~ 90

Author(s):

Neela D. Keshavan ◽

Puneet K. Chowdhary ◽

Donovan C. Haines ◽

Juan E. González

Keyword(s):

Quorum Sensing ◽

Medicago Sativa ◽

Sinorhizobium Meliloti ◽

Signal Molecules ◽

Bacterial Strains ◽

Signal Molecule ◽

Gram Negative ◽

Bacterial Quorum Sensing ◽

Bacterial Quorum ◽

Regulated Gene Expression

ABSTRACT Sinorhizobium meliloti is a gram-negative soil bacterium, capable of establishing a nitrogen-fixing symbiosis with its legume host, alfalfa (Medicago sativa). Quorum sensing plays a crucial role in this symbiosis, where it influences the nodulation process and the synthesis of the symbiotically important exopolysaccharide II (EPS II). S. meliloti has three quorum-sensing systems (Sin, Tra, and Mel) that use N-acyl homoserine lactones as their quorum-sensing signal molecule. Increasing evidence indicates that certain eukaryotic hosts involved in symbiotic or pathogenic relationships with gram-negative bacteria produce quorum-sensing-interfering (QSI) compounds that can cross-communicate with the bacterial quorum-sensing system. Our studies of alfalfa seed exudates suggested the presence of multiple signal molecules capable of interfering with quorum-sensing-regulated gene expression in different bacterial strains. In this work, we choose one of these QSI molecules (SWI) for further characterization. SWI inhibited violacein production, a phenotype that is regulated by quorum sensing in Chromobacterium violaceum. In addition, this signal molecule also inhibits the expression of the S. meliloti exp genes, responsible for the production of EPS II, a quorum-sensing-regulated phenotype. We identified this molecule as l-canavanine, an arginine analog, produced in large quantities by alfalfa and other legumes.

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Phage-Encoded LuxR-Type Receptors Responsive to Host-Produced Bacterial Quorum-Sensing Autoinducers

10.1101/577726 ◽

2019 ◽

Cited By ~ 1

Author(s):

Justin E. Silpe ◽

Bonnie L. Bassler

Keyword(s):

Quorum Sensing ◽

Pathogenic Bacteria ◽

Cell Communication ◽

Signal Molecules ◽

Host Bacterium ◽

Gram Negative ◽

Collective Behaviors ◽

Bacterial Quorum Sensing ◽

Genes Encoding ◽

Bacterial Quorum

AbstractQuorum sensing (QS) is a process of cell-to-cell communication that bacteria use to orchestrate collective behaviors. QS relies on the cell-density-dependent production, accumulation, and receptor-mediated detection of extracellular signaling molecules called autoinducers (AIs). Gram-negative bacteria commonly use N-acyl homoserine lactones (AHLs) as their AIs and they are detected by LuxR-type receptors. Often, LuxR-type receptors are insoluble when not bound to a cognate AI. In this report, we show that LuxR-type receptors are encoded on phage genomes and, in the cases we tested, the phage LuxR-type receptors bind to and are solubilized specifically by the AHL AI produced by the host bacterium. We do not yet know the viral activities that are controlled by these phage QS receptors, however, our observations, coupled with recent reports, suggest that their occurrence is more widespread than previously appreciated. Using receptor-mediated detection of QS AIs could enable phages to garner information concerning the population density status of their bacterial hosts. We speculate that such information can be exploited by phages to optimize the timing of execution of particular steps in viral infection.ImportanceBacteria communicate with chemical signal molecules to regulate group behaviors in a process called quorum sensing (QS). In this report, we find that genes encoding receptors for Gram-negative bacterial QS communication molecules are present on genomes of viruses that infect these bacteria. These viruses are called phages. We show that two phage-encoded receptors, like their bacterial counterparts, bind to the communication molecule produced by the host bacterium, suggesting that phages can “listen in” on their bacterial hosts. Interfering with bacterial QS and using phages to kill pathogenic bacteria represent attractive possibilities for development of new antimicrobials to combat pathogens that are resistant to traditional antibiotics. Our findings of interactions between phages and QS bacteria need consideration as new antimicrobial therapies are developed.

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Cross-kingdom signalling: exploitation of bacterial quorum sensing molecules by the green seaweed Ulva

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2007.2047 ◽

2007 ◽

Vol 362 (1483) ◽

pp. 1223-1233 ◽

Cited By ~ 95

Author(s):

Ian Joint ◽

Karen Tait ◽

Glen Wheeler

Keyword(s):

Quorum Sensing ◽

Calcium Influx ◽

Calcium Signalling ◽

Signal Molecules ◽

Wild Type ◽

Bacterial Quorum Sensing ◽

Green Seaweed ◽

Bacterial Quorum ◽

Lines Of Evidence

The green seaweed Ulva has been shown to detect signal molecules produced by bacteria. Biofilms that release N -acylhomoserine lactones (AHLs) attract zoospores—the motile reproductive stages of Ulva . The evidence for AHL involvement is based on several independent lines of evidence, including the observation that zoospores are attracted to wild-type bacteria that produce AHLs but are not attracted to mutants that do not produce signal molecules. Synthetic AHL also attracts zoospores and the attraction is lost in the presence of autoinducer inactivation (AiiA) protein. The mechanism of attraction is not chemotactic but involves chemokinesis. When zoospores detect AHLs, the swimming rate is reduced and this results in accumulation of cells at the source of the AHL. It has been demonstrated that the detection of AHLs results in calcium influx into the zoospore. This is the first example of a calcium signalling event in a eukaryote in response to bacterial quorum sensing molecules. The role of AHLs in the ecology of Ulva is discussed. It is probable that AHLs act as cues for the settlement of zoospores, rather than being directly involved as a signalling mechanism.

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