Inhibition of Pseudomonas aeruginosa ExsA DNA-Binding Activity by
            <i>N</i>
            -Hydroxybenzimidazoles

Marsden, Anne E.; King, Jessica M.; Spies, Maria; Kim, Oak K.; Yahr, Timothy L.

doi:10.1128/aac.02242-15

Cited by 25 publications

(20 citation statements)

References 43 publications

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“…N-hydroxybenzimidazole-binding pocket is located in the ExsA DNA-binding domain. Specific amino acid substitutions in this pocket resulted in altered sensitivity to N-hydroxybenzimidazoles, which enabled researchers to determine putative ligand-binding sites and helped designing higher-affinity inhibitors [48]. The interaction between N-hydroxybenzimidazoles and ExsA seems to be specific, because no effect has been observed on the binding to DNA of other virulence regulators, such as Vfr.…”

Section: Pathogenicity Related To the T3ssmentioning

confidence: 98%

See 1 more Smart Citation

Targeting the Type Three Secretion System in Pseudomonas aeruginosa

Anantharajah

Mingeot‐Leclercq

Bambeke

2016

Trends in Pharmacological Sciences

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Section: Pathogenicity Related To the T3ssmentioning

confidence: 98%

“…N-hydroxybenzimidazoles interact with the carboxy-terminal domain of ExsA, preventing its binding to promoter sites on DNA [47,48]. N-hydroxybenzimidazole-binding pocket is located in the ExsA DNA-binding domain.…”

Section: Pathogenicity Related To the T3ssmentioning

confidence: 99%

Targeting the Type Three Secretion System in Pseudomonas aeruginosa

Anantharajah

Mingeot‐Leclercq

Bambeke

2016

Trends in Pharmacological Sciences

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“…Several N-hydroxybenzimidazoles with 50% inhibitory concentrations (IC 50 s) in the low-micromolar range inhibit the DNA-binding activity of ExsA in vitro and T3SS-dependent toxicity toward macrophages (179). The N-hydroxybenzimidazoles interact with the carboxy-terminal DNA-binding domain of ExsA to inhibit DNA-binding activity (180). N-Hydroxybenzimidazoles also inhibit the DNA-binding activity of ExsA orthologs from Yersinia pestis, Aeromonas hydrophila, Photorhabdus luminescens, and Vibrio parahaemolyticus (180).…”

Section: Therapeutics and Inhibitors Of T3ss Gene Expressionmentioning

confidence: 99%

“…The N-hydroxybenzimidazoles interact with the carboxy-terminal DNA-binding domain of ExsA to inhibit DNA-binding activity (180). N-Hydroxybenzimidazoles also inhibit the DNA-binding activity of ExsA orthologs from Yersinia pestis, Aeromonas hydrophila, Photorhabdus luminescens, and Vibrio parahaemolyticus (180). Although active against ExsA in vitro, N-hydroxybenzimidazoles do not inhibit ExsA-dependent promoter activity in vivo when using either P. aeruginosa or E. coli reporter strains.…”

Section: Therapeutics and Inhibitors Of T3ss Gene Expressionmentioning

confidence: 99%

Fitting Pieces into the Puzzle of Pseudomonas aeruginosa Type III Secretion System Gene Expression

et al. 2019

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Type III secretion systems (T3SS) are widely distributed in Gram-negative microorganisms and critical for host-pathogen and host-symbiont interactions with plants and animals. Central features of the T3SS are a highly conserved set of secretion and translocation genes and contact dependence wherein host-pathogen interactions trigger effector protein delivery and serve as an inducing signal for T3SS gene expression. In addition to these conserved features, there are pathogen-specific properties that include a unique repertoire of effector genes and mechanisms to control T3SS gene expression. The Pseudomonas aeruginosa T3SS serves as a model system to understand transcriptional and posttranscriptional mechanisms involved in the control of T3SS gene expression. The central regulatory feature is a partner-switching system that controls the DNA-binding activity of ExsA, the primary regulator of T3SS gene expression. Superimposed upon the partner-switching mechanism are cyclic AMP and cyclic di-GMP signaling systems, two-component systems, global regulators, and RNA-binding proteins that have positive and negative effects on ExsA transcription and/or synthesis. In the present review, we discuss advances in our understanding of how these regulatory systems orchestrate the activation of T3SS gene expression in the context of acute infections and repression of the T3SS as P. aeruginosa adapts to and colonizes the cystic fibrosis airways.

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“…In the case of ExsA it is regulated through protein-protein contacts rather than small molecules. The inhibitors of DBD of ExsA belong to N-Hydroxybenzimidazole [14]. As mentioned above the DBD of these two proteins contain HTH motif, so there could be a common mechanism.…”

Section: Introductionmentioning

confidence: 99%

Mechanistic insights of the attenuation of quorum-sensing-dependent virulence factors of Pseudomonas aeruginosa: Molecular modeling of the interaction of taxifolin with transcriptional regulator LasR

Grabski

Tiratsuyan

2018

Preprint

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Pseudomonas aeruginosa is one of the most dangerous superbugs and is responsible for both acute and chronic infection. Current therapies are not effective because of biofilms that increase antibiotic resistance. Bacterial virulence and biofilm formation are regulated through a system called quorum sensing, which includes transcriptional regulators LasR and RhIR. These regulators are activated by their own natural autoinducers. Targeting this system is a promising strategy to combat bacterial pathogenicity. Flavonoids are very well known for their antimicrobial activity and taxifolin is one of them. It is also known that flavonoids inhibit Pseudomonas aeruginosa biofilm formation, but the mechanism of action is unknown. In the present study, we tried to analyse the mode of interactions of LasR with taxifolin. We used a combination of molecular docking, molecular dynamics simulations and machine learning techniques, which includes principal component and cluster analysis to study the interaction of the LasR protein with taxifolin. We show that taxifolin has two binding modes. One binding mode is the interaction with ligand binding domain. The second mode is the interaction with the "bridge", which is a cryptic binding site. It involves conserved amino acid interactions from multiple domains. Biochemical studies show hydroxyl group of ring A in flavonoids is necessary for inhibition. In our model the hydroxyl group ensures the formation of many hydrogen bonds during the second binding mode. Microsecond simulations also show the stability of the formed complex. This study may offer insights on how taxifolin inhibits LasR and the quorum sensing circuitry.

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Inhibition of Pseudomonas aeruginosa ExsA DNA-Binding Activity by N -Hydroxybenzimidazoles

Cited by 25 publications

References 43 publications

Targeting the Type Three Secretion System in Pseudomonas aeruginosa

Targeting the Type Three Secretion System in Pseudomonas aeruginosa

Fitting Pieces into the Puzzle of Pseudomonas aeruginosa Type III Secretion System Gene Expression

Mechanistic insights of the attenuation of quorum-sensing-dependent virulence factors of Pseudomonas aeruginosa: Molecular modeling of the interaction of taxifolin with transcriptional regulator LasR

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