Exploring the chemical space of ureidothiophene-2-carboxylic acids as inhibitors of the quorum sensing enzyme PqsD from Pseudomonas aeruginosa

Sahner, J. Henning; Empting, Martin; Kamal, Ahmed A. M.; Weidel, Elisabeth; Groh, Matthias F.; Börger, Carsten; Hartmann, Rolf W.

doi:10.1016/j.ejmech.2015.04.007

Cited by 40 publications

(43 citation statements)

References 38 publications

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“…Pseudomonas aeruginosa is one of the most common Gram-negative aerobic bacteria responsible for severe nosocomial infections. It is a multi-drug resistant germ, which greatly complicates the choice of antibiotic therapy [32][33][34][35]. Pseudomonas aeruginosa infections usually occur in immunocompromised patients or in anatomical sites with damaged natural barriers (skin, mucous membranes, etc.)…”

Section: Discussionmentioning

confidence: 99%

Incidence of pathogens infections in a Romanian Intensive Care Unit and sensitivity to antibiotics. A prospective single center study

Bedreag

Rogobete

Luca

et al. 2016

Acta Medica Marisiensis

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Introduction: Nosocomial infections represent one of the biggest challenges faced by clinicians in the intensive care unit (ICU) and is associated with high morbidity and mortality. Infections in ICU are most often very serious and represent often the cause of hospitalization in intensive care clinics. Aim of the study: This paper presents the incidence of nosocomial infections, and the sensitivity to antibiotics encountered in our ICU. Material and Methods: This prospective study was conducted for two years at the Clinic of Anesthesia and Intensive Care, Emergency County Hospital “Pius Brinzeu” Timisoara, Romania. All patients admitted to the ICU were analyzed in terms of signs and symptoms of bacterial infections. Results: A total of 1081 microbiological reports were recorded. Among these, 635 (58.70 %) represented infections in the respiratory tract, 201 (18.60 %) in the bloodstream, 100 (9.30 %) in genitourinary tract, and 10 (0.90 %) in the central nervous system. The top five most frequently identified pathogen in microbiological reports are Klebsiella sp (17.60 %), Acinetobacter sp (14.20 %), Proteus mirabilis (13.80 %), Pseudomonas aeruginosa (12.90 %), Staphylococcus aureus - MSSA (12.80%). Conclusions: In order to choose empirical treatment, international guidelines should be consulted according to each pathology and adapted to the sensitivity encountered in the microbiology reports of the Critical Care Unit.

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Section: Discussionmentioning

confidence: 99%

Incidence of pathogens infections in a Romanian Intensive Care Unit and sensitivity to antibiotics. A prospective single center study

Bedreag

Rogobete

Luca

et al. 2016

Acta Medica Marisiensis

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“…Consequently, PqsD has become a highly attractive target and a great amount of work pioneered by the Hartmann group has resulted in inhibitor discovery using a combination of in vitro assay, in silico modelling and chemical lead optimization. Examples of successful inhibitors are represented by the scaffolds of various 2-benzamidobenzoic acids [11,25–26], 2-nitrophenyl derivatives [27–29], ureidothiophene-2-carboxylic acids [24,30], and catechol-based compounds [31]. …”

Section: Resultsmentioning

confidence: 99%

Chemical probes for competitive profiling of the quorum sensing signal synthase PqsD of Pseudomonas aeruginosa

Prothiwa¹,

Szamosvári²,

Glasmacher³

et al. 2016

Beilstein J. Org. Chem.

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The human pathogen Pseudomonas aeruginosa uses the pqs quorum sensing system to coordinate the production of its broad spectrum of virulence factors to facilitate colonization and infection of its host. Hereby, the enzyme PqsD is a virulence related quorum sensing signal synthase that catalyzes the central step in the biosynthesis of the Pseudomonas quinolone signals HHQ and PQS. We developed a library of cysteine reactive chemical probes with an alkyne handle for fluorescence tagging and report the selective and highly sensitive in vitro labelling of the active site cysteine of this important enzyme. Interestingly, only one type of probe, with a reactive α-chloroacetamide was capable of covalently reacting with the active site. We demonstrated the potential of our probes in a competitive labelling platform where we screened a library of synthetic HHQ and PQS analogues with heteroatom replacements and found several inhibitors of probe binding that may represent promising scaffolds for the development of customized PqsD inhibitors as well as a chemical toolbox to investigate the activity and active site specificity of the enzyme.

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“…Alkylamine-modified cyclodextrins (Morohoshi et al, 2013 ) and homoserine lactone (HSL) aptamer (Figure 2H ; Zhao et al, 2013 ) inhibited the QS system through the formation of spatial conformations, whereas silicon dioxide nanoparticles functionalized with β-cyclodextrin reduced the luminous output of V. fischeri through binding of AHLs to the nanoparticles and removal of the AHLs from the immediate bacterial environment (Miller et al, 2015 ). Recently, ureidothiophene-2-carboxylic acids were described as inhibitors of the PQS-QS enzyme PqsD in P. aeruginosa (Sahner et al, 2015 ).…”

Section: Inhibition and Activation Of Qs Systems In Gram-negative Bacmentioning

confidence: 99%

Exploiting Quorum Sensing Interfering Strategies in Gram-Negative Bacteria for the Enhancement of Environmental Applications

Zhang

2016

Front. Microbiol.

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Quorum sensing (QS) is a widespread intercellular form of communication to coordinate physiological processes and cooperative activities of bacteria at the population level, and it depends on the production, secretion, and detection of small diffusible autoinducers, such as acyl-homoserine lactones (AHLs), auto-inducing oligo-peptides (AIPs) and autoinducer 2. In this review, the function of QS autoinducers of gram-negative bacteria in different aspects of wastewater treatment systems is examined. Based on research primarily performed over the past 10 years, QS involvement in the formation of biofilm and aerobic granules and changes of the microbial community and degradation/transformation pathways is discussed. In particular, the QS pathway in the role of bacterial infections and disease prevention in aquaculture is addressed. Interference of QS autoinducer-regulated pathways is considered potential treatment for a variety of environmentally related problems. This review is expected to serve as a stepping stone for further study and development strategies based on the mediation of QS-regulated pathways to enhance applications in both wastewater treatment systems and aquaculture.

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Exploring the chemical space of ureidothiophene-2-carboxylic acids as inhibitors of the quorum sensing enzyme PqsD from Pseudomonas aeruginosa

Cited by 40 publications

References 38 publications

Incidence of pathogens infections in a Romanian Intensive Care Unit and sensitivity to antibiotics. A prospective single center study

Incidence of pathogens infections in a Romanian Intensive Care Unit and sensitivity to antibiotics. A prospective single center study

Chemical probes for competitive profiling of the quorum sensing signal synthase PqsD of Pseudomonas aeruginosa

Exploiting Quorum Sensing Interfering Strategies in Gram-Negative Bacteria for the Enhancement of Environmental Applications

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