44 results on '"Soukarieh, Fadi"'
Search Results
2. Design, Synthesis, and Evaluation of New 1H-Benzo[d]imidazole Based PqsR Inhibitors as Adjuvant Therapy for Pseudomonas aeruginosa Infections
- Author
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Soukarieh, Fadi, primary, Mashabi, Alaa, additional, Richardson, William, additional, Oton, Eduard Vico, additional, Romero, Manuel, additional, Dubern, Jean-Frédéric, additional, Robertson, Shaun N., additional, Lucanto, Simone, additional, Markham-Lee, Zoe, additional, Sou, Tomás, additional, Kukavica-Ibrulj, Irena, additional, Levesque, Roger C., additional, Bergstrom, Christel A. S., additional, Halliday, Nigel, additional, Kellam, Barrie, additional, Emsley, Jonas, additional, Heeb, Stephan, additional, Williams, Paul, additional, Stocks, Michael J., additional, and Cámara, Miguel, additional
- Published
- 2024
- Full Text
- View/download PDF
3. Model-Based Drug Development in Pulmonary Delivery: Pharmacokinetic Analysis of Novel Drug Candidates for Treatment of Pseudomonas aeruginosa Lung Infection
- Author
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Sou, Tomás, Kukavica-Ibrulj, Irena, Soukarieh, Fadi, Halliday, Nigel, Levesque, Roger C., Williams, Paul, Stocks, Michael, Cámara, Miguel, Friberg, Lena E., and Bergström, Christel A.S.
- Published
- 2019
- Full Text
- View/download PDF
4. Design, synthesis and evaluation of mRNA cap analogues As eIF4E inhibitors
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Soukarieh, Fadi
- Subjects
615.58 - Abstract
The eukaryotic translation initiation factor 4E is an indispensable component of the cap-dependent translation initiation process. eIF4E binds to the mRNA cap and recruits, with the rest of initiation factors, the mRNA to the ribosomes. Under normal physiological conditions, eIF4E is the least abundant element of the translation initiation machinery. However, it has become evident that eIF4E is overexpressed in numerous tumour types leading to a translation enhancement of the oncogenic mRNAs. Thus it contributes to the initiation as well as the progression of the disease. Although eIF4E has been validated as a cancer drug target for over two decades, no drug-like eIF4E inhibitor has been developed, apart from the antiviral drug ribavirin. In this project, a set of nucleotide-based eIF4E inhibitors was designed and synthesised to mimic the mRNA cap structure in order to block the eIF4E cap binding slot. These molecules have a modified m7GTP structure at the level of the phosphate moiety as well as the N7 substituents, sites that are directly linked to the ligand affinity for eIF4E. A series of competitive and functional assays was then developed and optimised with the aim of assessing the ability of these ligands to sequester eIF4E from binding to capped mRNAs. These assays examined the inhibitors at multiple levels including the binding to a recombinant eIF4E, the effect on eIF4E functional role and the cellular influence on protein synthesis.
- Published
- 2013
5. Lipophilic activated ester prodrug approach for drug delivery to the intestinal lymphatic system
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Lee, Jong Bong, Zgair, Atheer, Malec, Jed, Kim, Tae Hwan, Kim, Min Gi, Ali, Joseph, Qin, Chaolong, Feng, Wanshan, Chiang, Manting, Gao, Xizhe, Voronin, Gregory, Garces, Aimie E., Lau, Chun Long, Chan, Ting-Hoi, Hume, Amy, McIntosh, Tecashanell M., Soukarieh, Fadi, Al-Hayali, Mohammed, Cipolla, Elena, Collins, Hilary M., Heery, David M., Shin, Beom Soo, Yoo, Sun Dong, Kagan, Leonid, Stocks, Michael J., Bradshaw, Tracey D., Fischer, Peter M., and Gershkovich, Pavel
- Published
- 2018
- Full Text
- View/download PDF
6. Design of nucleotide-mimetic and non-nucleotide inhibitors of the translation initiation factor eIF4E: Synthesis, structural and functional characterisation
- Author
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Soukarieh, Fadi, Nowicki, Matthew W., Bastide, Amandine, Pöyry, Tuija, Jones, Carolyn, Dudek, Kate, Patwardhan, Geetanjali, Meullenet, François, Oldham, Neil J., Walkinshaw, Malcolm D., Willis, Anne E., and Fischer, Peter M.
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- 2016
- Full Text
- View/download PDF
7. Probing Interkingdom Signaling Molecules via Liquid Extraction Surface Analysis–Mass Spectrometry
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Robertson, Shaun N., primary, Soukarieh, Fadi, additional, White, Thomas M., additional, Camara, Miguel, additional, Romero, Manuel, additional, and Griffiths, Rian L., additional
- Published
- 2023
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- View/download PDF
8. Design of Quorum Sensing Inhibitor–Polymer Conjugates to Penetrate Pseudomonas aeruginosa Biofilms
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Soukarieh, Fadi, primary, Gurnani, Pratik, additional, Romero, Manuel, additional, Halliday, Nigel, additional, Stocks, Michael, additional, Alexander, Cameron, additional, and Cámara, Miguel, additional
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- 2023
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9. Design and Evaluation of New Quinazolin-4(3 H)-one Derived PqsR Antagonists as Quorum Sensing Quenchers in Pseudomonas aeruginosa
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Soukarieh, Fadi, Mashabi, Alaa, Richardson, William, Oton, Eduard Vico, Romero, Manuel, Grossman, Scott, Sou, Tomas, Liu, Ruiling, Halliday, Nigel, Kukavica-Ibrulj, Irena, Levesque, Roger C., Kellam, Barrie, Emsley, Jonas, Heeb, Stephan, Williams, Paul, Stocks, Michael J., Roberston, Shaun N., and Bergstrom, Christel A. S.
- Subjects
Infectious Diseases - Abstract
P. aeruginosa (PA) continues to pose a threat to global public health due to its high levels of antimicrobial resistance (AMR). The ongoing AMR crisis has led to an alarming shortage of effective treatments for resistant microbes, and hence there is a pressing demand for the development of novel antimicrobial interventions. The potential use of antivirulence therapeutics to tackle bacterial infections has attracted considerable attention over the past decades as they hamper the pathogenicity of target microbes with reduced selective pressure, minimizing the emergence of resistance. One such approach is to interfere with the PA pqs quorum sensing system which upon the interaction of PqsR, a Lys-R type transcriptional regulator, with its cognate signal molecules 4-hydroxy-2-heptylquinoline (HHQ) and 2-heptyl-3-hydroxy-4-quinolone (PQS), governs multiple virulence traits and host-microbe interactions. In this study, we report the hit identification and optimization of PqsR antagonists using virtual screening coupled with whole cell assay validation. The optimized hit compound 61 ((R)-2-(4-(3-(6-chloro-4-oxoquinazolin-3(4H)-yl)-2-hydroxypropoxy)phenyl)acetonitrile) was found to inhibit the expression of the PA PpqsA promoter controlled by PqsR with an IC50 of 1 μM. Using isothermal titration calorimetry, a Kd of 10 nM for the PqsR ligand binding domain (PqsRLBD) was determined for 61. Furthermore, the crystal structure of 61 with PqsRLBD was attained with a resolution of 2.65 Å. Compound 61 significantly reduced levels of pyocyanin, PQS, and HHQ in PAO1-L, PA14 lab strains and PAK6085 clinical isolate. Furthermore, this compound potentiated the effect of ciprofloxacin in early stages of biofilm treatment and in Galleria mellonella infected with PA. Altogether, this data shows 61 as a potent PqsR inhibitor with potential for hit to lead optimization toward the identification of a PA QS inhibitor which can be advanced into preclinical development.
- Published
- 2021
10. Postprandial administration but not controlled release in the colon increases oral bioavailability of DF030263, a promising drug candidate for chronic lymphocytic leukemia
- Author
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Bong Lee, Jong, Zang, Xiaowei, Zgair, Atheer, Qian Ooi, Ting, Foley, David W, Voronin, Gregory, Kagan, Leonid, Soukarieh, Fadi, Gao, Rui, Shao, Hao, Tying Soh, Wan, Hwan Kim, Tae, Gi Kim, Min, Yun, Hwi-yeol, Wilson, Anthony J., Fischer, Peter M., and Gershkovich, Pavel
- Abstract
For treatment of chronic cancers, the oral administration route is preferred as it provides numerous advantages over other delivery routes. However, these benefits of oral chemotherapy can be limited due to unfavorable pharmacokinetics. Accordingly, pharmacokinetic development of chemotherapeutic agents is crucial to the improvement of cancer treatment. In this study, assessment and optimization of biopharmaceutical properties of a promising drug candidate for cyclin-dependent kinase 9 (CDK9) inhibitor (DF030263) was performed to promote oral delivery. Oral bioavailability of DF030263 in fasted rats was 23.8%, and a distinct double-peak phenomenon was observed. A two-site absorption windows mechanism was proposed as a possible explanation to the phenomenon. The two-site absorption window hypothesis was supported by in vitro solubility assays in biorelevant fluids with different pH levels, as well as by in silico simulation by GastroPlusTM. Controlled release to the colon was conducted in rats in order to exploit the colonic absorption window but did not improve the oral bioavailability. On the other hand, oral administration at postprandial conditions in rats (performed based on the high in vitro solubility in fed state simulated fluid and reduced pH-dependency) resulted in an almost 3-fold increase in bioavailability to 63.6%. In conclusion, this study demonstrates an efficient in vitro-in vivo-in silico drug development approach for improving the oral bioavailability of DF030263, a promising candidate for the treatment of chronic lymphocytic leukemia.
- Published
- 2021
11. Design and Evaluation of New Quinazolin-4(3H)-one Derived PqsR Antagonists as Quorum Sensing Quenchers in Pseudomonas aeruginosa
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Soukarieh, Fadi, primary, Mashabi, Alaa, additional, Richardson, William, additional, Oton, Eduard Vico, additional, Romero, Manuel, additional, Roberston, Shaun N., additional, Grossman, Scott, additional, Sou, Tomas, additional, Liu, Ruiling, additional, Halliday, Nigel, additional, Kukavica-Ibrulj, Irena, additional, Levesque, Roger C., additional, Bergstrom, Christel A. S., additional, Kellam, Barrie, additional, Emsley, Jonas, additional, Heeb, Stephan, additional, Williams, Paul, additional, Stocks, Michael J., additional, and Cámara, Miguel, additional
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- 2021
- Full Text
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12. Administration in fed state but not controlled release in the colon increases oral bioavailability of DF030263, a promising drug candidate for chronic lymphocytic leukemia
- Author
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Lee, Jong Bong, primary, Zang, Xiaowei, additional, Zgair, Atheer, additional, Ooi, Ting Qian, additional, Foley, David W., additional, Voronin, Gregory, additional, Kagan, Leonid, additional, Soukarieh, Fadi, additional, Gao, Rui, additional, Shao, Hao, additional, Soh, Wan Tying, additional, Kim, Tae Hwan, additional, Kim, Min Gi, additional, Yun, Hwi-yeol, additional, Wilson, Anthony J., additional, Fischer, Peter M., additional, and Gershkovich, Pavel, additional
- Published
- 2021
- Full Text
- View/download PDF
13. Design and Evaluation of New Quinazolin-4(3H)-one Derived PqsR Antagonists as Quorum Sensing Quenchers in Pseudomonas aeruginosa
- Author
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Soukarieh, Fadi, Mashabi, Alaa, Richardson, William, Oton, Eduard Vico, Romero, Manuel, Roberston, Shaun N., Grossman, Scott, Sou, Tomas, Liu, Ruiling, Halliday, Nigel, Kukavica-Ibrulj, Irena, Levesque, Roger C., Bergström, Christel, Kellam, Barrie, Emsley, Jonas, Heeb, Stephan, Williams, Paul, Stocks, Michael J., Camara, Miguel, Soukarieh, Fadi, Mashabi, Alaa, Richardson, William, Oton, Eduard Vico, Romero, Manuel, Roberston, Shaun N., Grossman, Scott, Sou, Tomas, Liu, Ruiling, Halliday, Nigel, Kukavica-Ibrulj, Irena, Levesque, Roger C., Bergström, Christel, Kellam, Barrie, Emsley, Jonas, Heeb, Stephan, Williams, Paul, Stocks, Michael J., and Camara, Miguel
- Abstract
P. aeruginosa (PA) continues to pose a threat to global public health due to its high levels of antimicrobial resistance (AMR). The ongoing AMR crisis has led to an alarming shortage of effective treatments for resistant microbes, and hence there is a pressing demand for the development of novel antimicrobial interventions. The potential use of antivirulence therapeutics to tackle bacterial infections has attracted considerable attention over the past decades as they hamper the pathogenicity of target microbes with reduced selective pressure, minimizing the emergence of resistance. One such approach is to interfere with the PA pqs quorum sensing system which upon the interaction of PqsR, a Lys-R type transcriptional regulator, with its cognate signal molecules 4-hydroxy-2-heptylquinoline (HHQ) and 2-heptyl-3-hydroxy-4-quinolone (PQS), governs multiple virulence traits and host-microbe interactions. In this study, we report the hit identification and optimization of PqsR antagonists using virtual screening coupled with whole cell assay validation. The optimized hit compound 61 ((R)-2-(4-(3-(6-chloro-4-oxoquinazolin-3(4H)-yl)-2-hydroxypropoxy)phenyl)acetonitrile) was found to inhibit the expression of the PA P-pqsA promoter controlled by PqsR with an IC50 of 1 mu M. Using isothermal titration calorimetry, a K-d of 10 nM for the P-qsR ligand binding domain (PqsR(LBD)) was determined for 61. Furthermore, the crystal structure of 61 with PqsR(LBD) was attained with a resolution of 2.65 angstrom. Compound 61 significantly reduced levels of pyocyanin, PQS, and HHQ in PAO1-L, PA14 lab strains and PAK6085 clinical isolate. Furthermore, this compound potentiated the effect of ciprofloxacin in early stages of biofilm treatment and in Galleria mellonella infected with PA. Altogether, this data shows 61 as a potent PqsR inhibitor with potential for hit to lead optimization toward the identification of a PA QS inhibitor which can be advanced into preclinical development.
- Published
- 2021
- Full Text
- View/download PDF
14. Model-Informed Drug Discovery and Development in Pulmonary Delivery: Biopharmaceutical Pharmacometric Modeling for Formulation Evaluation of Pulmonary Suspensions
- Author
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Soukarieh, Fadi, Williams, Paul, and Stocks, Michael J.
- Abstract
Copyright © 2020 American Chemical Society. For respiratory conditions, targeted drug delivery to the lungs could produce higher local concentrations with reduced risk of adverse events compared to systemic administration. Despite the increasing interest in pulmonary delivery, the pharmacokinetics (PK) of drugs following pulmonary administration remains to be elucidated. In this context, the application of modeling and simulation methodologies to characterize PK properties of compounds following pulmonary administration remains a scarcity. Pseudomonas aeruginosa (PA) lung infections are resistant to many of the current antibiotic therapies. Targeted treatments for pulmonary delivery could be particularly beneficial for these local conditions. In this study, we report the application of biopharmaceutical pharmacometrics (BPMX) for the analysis of PK data from three investigational antimicrobial agents following pulmonary administration of a suspension formulation. The observed drug concentration-time profiles in lungs and plasma of the compound series were combined for simultaneous analysis and modeling. The developed model describes the PK data, taking into account formulation properties, and provides a mechanism to predict dissolved drug concentrations in the lungs available for activity. The model was then used to evaluate formulation effects and the impact of variability on total and dissolved drug concentrations in lungs and plasma. The predictions suggest that these therapies for lung delivery should ideally be delivered in a sustained release formulation with high solubility for maximum local exposure in lungs for efficacy, with rapid systemic clearance in plasma for reduced risk of unwanted systemic adverse effects. This work shows the potential benefits of BPMX and the role it can play to support drug discovery and development in pulmonary delivery.
- Published
- 2020
15. Model-Informed Drug Discovery and Development in Pulmonary Delivery : Biopharmaceutical Pharmacometric Modeling for Formulation Evaluation of Pulmonary Suspensions
- Author
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Sou, Tomás, Soukarieh, Fadi, Williams, Paul, Stocks, Michael J., Camara, Miguel, Bergström, Christel, Sou, Tomás, Soukarieh, Fadi, Williams, Paul, Stocks, Michael J., Camara, Miguel, and Bergström, Christel
- Abstract
For respiratory conditions, targeted drug delivery to the lungs could produce higher local concentrations with reduced risk of adverse events compared to systemic administration. Despite the increasing interest in pulmonary delivery, the pharmacokinetics (PK) of drugs following pulmonary administration remains to be elucidated. In this context, the application of modeling and simulation methodologies to characterize PK properties of compounds following pulmonary administration remains a scarcity. Pseudomonas aeruginosa (PA) lung infections are resistant to many of the current antibiotic therapies. Targeted treatments for pulmonary delivery could be particularly beneficial for these local conditions. In this study, we report the application of biopharmaceutical pharmacometrics (BPMX) for the analysis of PK data from three investigational antimicrobial agents following pulmonary administration of a suspension formulation. The observed drug concentration-time profiles in lungs and plasma of the compound series were combined for simultaneous analysis and modeling. The developed model describes the PK data, taking into account formulation properties, and provides a mechanism to predict dissolved drug concentrations in the lungs available for activity. The model was then used to evaluate formulation effects and the impact of variability on total and dissolved drug concentrations in lungs and plasma. The predictions suggest that these therapies for lung delivery should ideally be delivered in a sustained release formulation with high solubility for maximum local exposure in lungs for efficacy, with rapid systemic clearance in plasma for reduced risk of unwanted systemic adverse effects. This work shows the potential benefits of BPMX and the role it can play to support drug discovery and development in pulmonary delivery.
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- 2020
- Full Text
- View/download PDF
16. Hit Identification of New Potent PqsR Antagonists as Inhibitors of Quorum Sensing in Planktonic and Biofilm Grown Pseudomonas aeruginosa
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Soukarieh, Fadi, Liu, Ruiling, Romero, Manuel, Roberston, Shaun N., Richardson, William, Lucanto, Simone, Oton, Eduard Vico, Qudus, Naim Ruhul, Mashabi, Alaa, Grossman, Scott, Ali, Sadiqur, Sou, Tomás, Kukavica-Ibrulj, Irena, Levesque, Roger C., Bergström, Christel, Halliday, Nigel, Mistry, Shailesh N., Emsley, Jonas, Heeb, Stephan, Williams, Paul, Camara, Miguel, Stocks, Michael J., Soukarieh, Fadi, Liu, Ruiling, Romero, Manuel, Roberston, Shaun N., Richardson, William, Lucanto, Simone, Oton, Eduard Vico, Qudus, Naim Ruhul, Mashabi, Alaa, Grossman, Scott, Ali, Sadiqur, Sou, Tomás, Kukavica-Ibrulj, Irena, Levesque, Roger C., Bergström, Christel, Halliday, Nigel, Mistry, Shailesh N., Emsley, Jonas, Heeb, Stephan, Williams, Paul, Camara, Miguel, and Stocks, Michael J.
- Abstract
Current treatments for Pseudomonas aeruginosa infections are becoming less effective because of the increasing rates of multi-antibiotic resistance. Pharmacological targeting of virulence through inhibition of quorum sensing (QS) dependent virulence gene regulation has considerable therapeutic potential. In P. aeruginosa, the pqs QS system regulates the production of multiple virulence factors as well as biofilm maturation and is a promising approach for developing antimicrobial adjuvants for combatting drug resistance. In this work, we report the hit optimisation for a series of potent novel inhibitors of PqsR, a key regulator of the pqs system, bearing a 2-((5-methyl-5H-[1,2,4]triazino[5,6-b]indol-3-yl)thio) acetamide scaffold. The initial hit compound 7 (PAO1-L IC50 0.98 +/- 0.02 mu M, PA14 inactive at 10 mu M) was obtained through a virtual screening campaign performed on the PqsR ligand binding domain using the University of Nottingham Managed Chemical Compound Collection. Hit optimisation gave compounds with enhanced potency against strains PAO1-L and PA14, evaluated using P. aeruginosa pqs-based QS bioreporter assays. Compound 40 (PAO1-L IC50 0.25 +/- 0.12 mu M, PA14 IC50 0.34 +/- 0.03 mu M) is one of the most potent PqsR antagonists reported showing significant inhibition of P. aeruginosa pyocyanin production and pqs system signaling in both planktonic cultures and biofilms. The co-crystal structure of 40 with the PqsR ligand binding domain revealed the specific binding interactions occurring between inhibitor and this key regulatory protein.
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- 2020
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17. Model-Informed Drug Discovery and Development in Pulmonary Delivery: Biopharmaceutical Pharmacometric Modeling for Formulation Evaluation of Pulmonary Suspensions
- Author
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Sou, Tomás, primary, Soukarieh, Fadi, additional, Williams, Paul, additional, Stocks, Michael J., additional, Cámara, Miguel, additional, and Bergström, Christel A. S., additional
- Published
- 2020
- Full Text
- View/download PDF
18. Hit Identification of New Potent PqsR Antagonists as Inhibitors of Quorum Sensing in Planktonic and Biofilm Grown Pseudomonas aeruginosa
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Soukarieh, Fadi, primary, Liu, Ruiling, additional, Romero, Manuel, additional, Roberston, Shaun N., additional, Richardson, William, additional, Lucanto, Simone, additional, Oton, Eduard Vico, additional, Qudus, Naim Ruhul, additional, Mashabi, Alaa, additional, Grossman, Scott, additional, Ali, Sadiqur, additional, Sou, Tomás, additional, Kukavica-Ibrulj, Irena, additional, Levesque, Roger C., additional, Bergström, Christel A. S., additional, Halliday, Nigel, additional, Mistry, Shailesh N., additional, Emsley, Jonas, additional, Heeb, Stephan, additional, Williams, Paul, additional, Cámara, Miguel, additional, and Stocks, Michael J., additional
- Published
- 2020
- Full Text
- View/download PDF
19. Model-based drug development in pulmonary delivery: pharmacokinetic analysis of novel drug candidates for treatment of Pseudomonas aeruginosa lung infection
- Author
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Kukavica-Ibrulj, Irena, Soukarieh, Fadi, Halliday, Nigel, Levesque, Roger C., Williams, Paul, Stocks, Michael, and Friberg, Lena E.
- Subjects
solubility ,disposition ,distribution ,PK/PD modeling ,simulations ,pulmonary drug delivery ,preclinical pharmacokineticsabsorption ,pharmacometrics ,metabolic clearance - Abstract
Antibiotic resistance is a major public health threat worldwide. In particular, about 80% of cystic fibrosis patients have chronic Pseudomonas aeruginosa (PA) lung infection resistant to many current antibiotics. We are therefore developing a novel class of anti-virulence agents, quorum sensing inhibitors (QSIs), which inhibit biofilm formation and sensitise PA to antibiotic treatments. For respiratory conditions, targeted delivery to the lung could achieve higher local concentrations with reduced risk of adverse systemic events. In this study, we report the pharmacokinetics of three prototype QSIs after pulmonary delivery, and the simultaneous analysis of the drug concentration-time profiles from bronchoalveolar lavage, lung homogenate and plasma samples, using a modelling approach. In addition to facilitating the direct comparison and selection of drug candidates, the developed model was used for dosing simulation studies to predict in vivo exposure following different dosing scenarios. The results suggest that systemic clearance has limited impact on local drug exposure in the lung after pulmonary delivery. Therefore, we believe that novel QSIs designed for pulmonary delivery as targeted treatment for respiratory conditions should ideally have a long residence time in the lung for local efficacy with rapid clearance after systemic absorption for reduced risk of adverse systemic events.
- Published
- 2019
20. In Silico and in Vitro-Guided Identification of Inhibitors of Alkylquinolone-Dependent Quorum Sensing in Pseudomonas aeruginosa
- Author
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Soukarieh, Fadi, Vico Oton, Eduard, Gomes, Janice, Halliday, Nigel, de Pilar Crespo, Maria, Insuasty, Braulio, Abonia, Rodrigo, Quiroga, Jairo, Heeb, Stephan, Williams, Paul, and Stocks, Michael
- Subjects
PqsR ,alkylquinolone ,quorum sensing inhibition ,Pseudomonas aeruginosa ,MvfR ,Pseudomonas quinolone signal (PQS) ,biochemical phenomena, metabolism, and nutrition - Abstract
Pseudomonas aeruginosa is a major opportunistic pathogen in cystic fibrosis, wound and nosocomial infections, posing a serious burden to public health, due to its antibiotic resistance. The P. aeruginosa Pseudomonas Quinolone System (pqs) quorum sensing system, driven by the activation of the transcriptional regulator, PqsR (MvfR) by alkylquinolone (AQ) signal molecules, is a key player in the regulation of virulence and a potential target for the development of novel antibacterial agents. In this study, we performed in silico docking analysis, coupled with screening using a P. aeruginosa mCTX::PpqsA-lux chromosomal promoter fusion, to identify a series of new PqsR antagonists. The hit compounds inhibited pyocyanin and alkylquinolone signal molecule production in P. aeruginosa PAO1-L and PA14 strains. The inhibitor Ia, which showed the highest activity in PA14, reduced biofilmformation in PAO1-L and PA14, increasing their sensitivity to tobramycin. Furthermore, the hepatic and plasma stabilities for these compounds were determined in both rat and human in vitro microsomal assays, to gain a further understanding of their therapeutic potential. This work has uncovered a new class of P. aeruginosa PqsR antagonists with potential for hit to lead optimisation in the search for quorum sensing inhibitors for future anti-infective drug discovery programs.
- Published
- 2018
21. Pseudomonas aeruginosa Quorum Sensing Systems as Drug Discovery Targets: Current Position and Future Perspectives
- Author
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Soukarieh, Fadi, primary, Williams, Paul, additional, Stocks, Michael J, additional, and Cámara, Miguel, additional
- Published
- 2018
- Full Text
- View/download PDF
22. Pseudomonas aeruginosaQuorum Sensing Systems as Drug Discovery Targets: Current Position and Future Perspectives
- Author
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Soukarieh, Fadi, Williams, Paul, Stocks, Michael J, and Cámara, Miguel
- Abstract
Antimicrobial resistance (AMR) is a serious threat to public health globally, manifested by the frequent emergence of multidrug resistant pathogens that render current chemotherapy inadequate. Health organizations worldwide have recognized the severity of this crisis and implemented action plans to contain its adverse consequences and prolong the utility of conventional antibiotics. Hence, there is a pressing need for new classes of antibacterial agents with novel modes of action. Quorum sensing (QS), a communication system employed by bacterial populations to coordinate virulence gene expression, is a potential target that has been intensively investigated over the past decade. This Perspective will focus on recent advances in targeting the three main quorum sensing systems (las, rhl, and pqs) of a major opportunistic human pathogen, Pseudomonas aeruginosa, and will specifically evaluate the medicinal chemistry strategies devised to develop QS inhibitors from a drug discovery perspective.
- Published
- 2018
- Full Text
- View/download PDF
23. Design of nucleotide-mimetic and non-nucleotide inhibitors of the translation initiation factor eIF4E: Synthesis, structural and functional characterisation
- Author
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Soukarieh, Fadi, Nowicki, Matthew W, Bastide, Amandine, Pöyry, Tuija, Jones, Carolyn, Dudek, Kate, Patwardhan, Geetanjali, Meullenet, François, Oldham, Neil J, Walkinshaw, Malcolm D, Willis, Anne E, and Fischer, Peter M
- Subjects
Models, Molecular ,RNA Caps ,mRNA translation ,Nucleotides ,Protein Conformation ,Thiourea ,Chemistry Techniques, Synthetic ,3. Good health ,Eukaryotic Initiation Factor-4E ,Cap-binding inhibitor ,Biomimetic Materials ,eIF4E ,Drug Design ,Animals ,Rabbits ,Protein synthesis ,Cancer - Abstract
Eukaryotic translation initiation factor 4E (eIF4E) is considered as the corner stone in the cap-dependent translation initiation machinery. Its role is to recruit mRNA to the ribosome through recognition of the 5'-terminal mRNA cap structure (m7GpppN, where G is guanosine, N is any nucleotide). eIF4E is implicated in cell transformation, tumourigenesis, and angiogenesis by facilitating translation of oncogenic mRNAs; it is thus regarded as an attractive anticancer drug target. We have used two approaches to design cap-binding inhibitors of eIF4E by modifying the N7-substituent of m7GMP and replacing the phosphate group with isosteres such as squaramides, sulfonamides, and tetrazoles, as well as by structure-based virtual screening aimed at identifying non-nucleotide cap-binding antagonists. Phosphomimetic nucleotide derivatives and highly ranking virtual hits were evaluated in a series of in vitro and cell-based assays to identify the first non-nucleotide eIF4E cap-binding inhibitor with activities in cell-based assays, N-[(5,6-dihydro-6-oxo-1,3-dioxolo[4,5-g]quinolin-7-yl)methyl]-N'-(2-methyl-propyl)-N-(phenyl-methyl)thiourea (14), including down-regulation of oncogenic proteins and suppression of RNA incorporation into polysomes. Although we did not observe cellular activity with any of our modified m7GMP phosphate isostere compounds, we obtained X-ray crystallography structures of three such compounds in complex with eIF4E, 5'-deoxy-5'-(1,2-dioxo-3-hydroxycyclobut-3-en-4-yl)amino-N7-methyl-guanosine (4a), N7-3-chlorobenzyl-5'-deoxy-5'-(1,2-dioxo-3-hydroxy-cyclobut-3-en-4-yl)amino-guanosine (4f), and N7-benzyl-5'-deoxy-5'-(trifluoromethyl-sulfamoyl)guanosine (7a). Collectively, the data we present on structure-based design of eIF4E cap-binding inhibitors should facilitate the optimisation of such compounds as potential anticancer agents.
24. Pseudomonas aeruginosa quorum sensing systems as drug discovery targets: current position and future perspectives
- Author
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Soukarieh, Fadi, Williams, Paul, Stocks, Michael John, Camara, Miguel, Soukarieh, Fadi, Williams, Paul, Stocks, Michael John, and Camara, Miguel
- Abstract
Antimicrobial resistance (AMR) is a serious threat to public health globally, manifested by the frequent emergence of multi-drug resistant pathogens that render current chemotherapy inadequate. Health organizations worldwide have recognized the severity of this crisis and implemented action plans to contain its adverse consequences and prolong the utility of conventional antibiotics. Hence, there is a pressing need for new classes of antibacterial agents with novel modes of action. Quorum sensing (QS), a communication system employed by bacterial populations to co-ordinate virulence gene expression, is a potential target that has been intensively investigated over the last decade. This Perspective will focus on recent advances in targeting the three main quorum sensing systems (las, rhl and pqs) of a major opportunistic human pathogen, Pseudomonas aeruginosa, and will specifically evaluate the medicinal chemistry strategies devised to develop QS inhibitors from a drug discovery perspective.
- Full Text
- View/download PDF
25. Pseudomonas aeruginosa quorum sensing systems as drug discovery targets: current position and future perspectives
- Author
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Soukarieh, Fadi, Williams, Paul, Stocks, Michael John, Camara, Miguel, Soukarieh, Fadi, Williams, Paul, Stocks, Michael John, and Camara, Miguel
- Abstract
Antimicrobial resistance (AMR) is a serious threat to public health globally, manifested by the frequent emergence of multi-drug resistant pathogens that render current chemotherapy inadequate. Health organizations worldwide have recognized the severity of this crisis and implemented action plans to contain its adverse consequences and prolong the utility of conventional antibiotics. Hence, there is a pressing need for new classes of antibacterial agents with novel modes of action. Quorum sensing (QS), a communication system employed by bacterial populations to co-ordinate virulence gene expression, is a potential target that has been intensively investigated over the last decade. This Perspective will focus on recent advances in targeting the three main quorum sensing systems (las, rhl and pqs) of a major opportunistic human pathogen, Pseudomonas aeruginosa, and will specifically evaluate the medicinal chemistry strategies devised to develop QS inhibitors from a drug discovery perspective.
- Full Text
- View/download PDF
26. Lipophilic activated ester prodrug approach for drug delivery to the intestinal lymphatic system
- Author
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Lee, Jong Bong, Zgair, Atheer, Malec, Jed, Kim, Tae Hwan, Kim, Min Gi, Ali, Joseph, Qin, Chaolong, Feng, Wanshan, Chiang, Manting, Gao, Xizhe, Voronin, Gregory, Garces, Aimie, Lau, Chun Long, Chan, Ting-Hoi, Hume, Amy, McIntosh, Tecashanell M., Soukarieh, Fadi, Al-Hayali, Mohammed, Cipolla, Elena, Collins, Hilary M., Heery, David M., Shin, Beom Soo, Yoo, Sun Dong, Kagan, Leonid, Stocks, Michael J., Bradshaw, Tracey D., Fischer, Peter M., Gershkovich, Pavel, Lee, Jong Bong, Zgair, Atheer, Malec, Jed, Kim, Tae Hwan, Kim, Min Gi, Ali, Joseph, Qin, Chaolong, Feng, Wanshan, Chiang, Manting, Gao, Xizhe, Voronin, Gregory, Garces, Aimie, Lau, Chun Long, Chan, Ting-Hoi, Hume, Amy, McIntosh, Tecashanell M., Soukarieh, Fadi, Al-Hayali, Mohammed, Cipolla, Elena, Collins, Hilary M., Heery, David M., Shin, Beom Soo, Yoo, Sun Dong, Kagan, Leonid, Stocks, Michael J., Bradshaw, Tracey D., Fischer, Peter M., and Gershkovich, Pavel
- Abstract
The intestinal lymphatic system plays an important role in the pathophysiology of multiple diseases including lymphomas, cancer metastasis, autoimmune diseases, and human immunodeficiency virus (HIV) infection. It is thus an important compartment for delivery of drugs in order to treat diseases associated with the lymphatic system. Lipophilic prodrug approaches have been used in the past to take advantage of the intestinal lymphatic transport processes to deliver drugs to the intestinal lymphatics. Most of the approaches previously adopted were based on very bulky prodrug moieties such as those mimicking triglycerides (TG). We now report a study in which a lipophilic prodrug approach was used to efficiently deliver bexarotene (BEX) and retinoic acid (RA) to the intestinal lymphatic system using activated ester prodrugs. A range of carboxylic ester prodrugs of BEX were designed and synthesised and all of the esters showed improved association with chylomicrons, which indicated an improved potential for delivery to the intestinal lymphatic system. The conversion rate of the prodrugs to BEX was the main determinant in delivery of BEX to the intestinal lymphatics, and activated ester prodrugs were prepared to enhance the conversion rate. As a result, an 4-(hydroxymethyl)-1,3-dioxol-2-one ester prodrug of BEX was able to increase the exposure of the mesenteric lymph nodes (MLNs) to BEX 17-fold compared to when BEX itself was administered. The activated ester prodrug approach was also applied to another drug, RA, where the exposure of the MLNs was increased 2.4-fold through the application of a similar cyclic activated prodrug. Synergism between BEX and RA was also demonstrated in vitro by cell growth inhibition assays using lymphoma cell lines. In conclusion, the activated ester prodrug approach results in efficient delivery of drugs to the intestinal lymphatic system, which could benefit patients affected by a large number of pathological conditions.
- Full Text
- View/download PDF
27. In silico and in vitro-guided identification of inhibitors of alkylquinolone-dependent quorum sensing in Pseudomonas aeruginosa
- Author
-
Soukarieh, Fadi, Oton, Eduard Vico, Dubern, Jean-Frédéric, Gomes, Janice, Halliday, Nigel, de Pilar Crespo, Maria, Ramírez-Prada, Jonathan, Insuasty, Braulio, Abonia, Rodrigo, Quiroga, Jairo, Heeb, Stephan, Williams, Paul, Stocks, Michael J., Cámara, Miguel, Soukarieh, Fadi, Oton, Eduard Vico, Dubern, Jean-Frédéric, Gomes, Janice, Halliday, Nigel, de Pilar Crespo, Maria, Ramírez-Prada, Jonathan, Insuasty, Braulio, Abonia, Rodrigo, Quiroga, Jairo, Heeb, Stephan, Williams, Paul, Stocks, Michael J., and Cámara, Miguel
- Abstract
Pseudomonas aeruginosa is a major opportunistic pathogen in cystic fibrosis, wound and nosocomial infections, posing a serious burden to public health, due to its antibiotic resistance. The P. aeruginosa Pseudomonas Quinolone System (pqs) quorum sensing system, driven by the activation of the transcriptional regulator, PqsR (MvfR) by alkylquinolone (AQ) signal molecules, is a key player in the regulation of virulence and a potential target for the development of novel antibacterial agents. In this study, we performed in silico docking analysis, coupled with screening using a P. aeruginosa mCTX::PpqsA-lux chromosomal promoter fusion, to identify a series of new PqsR antagonists. The hit compounds inhibited pyocyanin and alkylquinolone signal molecule production in P. aeruginosa PAO1-L and PA14 strains. The inhibitor Ia, which showed the highest activity in PA14, reduced biofilmformation in PAO1-L and PA14, increasing their sensitivity to tobramycin. Furthermore, the hepatic and plasma stabilities for these compounds were determined in both rat and human in vitro microsomal assays, to gain a further understanding of their therapeutic potential. This work has uncovered a new class of P. aeruginosa PqsR antagonists with potential for hit to lead optimisation in the search for quorum sensing inhibitors for future anti-infective drug discovery programs.
- Full Text
- View/download PDF
28. Design of nucleotide-mimetic and non-nucleotide inhibitors of the translation initiation factor eIF4E: synthesis, structural and functional characterisation
- Author
-
Soukarieh, Fadi, Nowicki, Matthew W., Bastide, Amandine, Poyry, Tuija, Jones, Carolyn, Dudek, Kate, Patwardhan, Geetanjali, Meullenet, François, Oldham, Neil J., Walkinshaw, Malcolm D., Willis, Anne E., Fischer, Peter M., Soukarieh, Fadi, Nowicki, Matthew W., Bastide, Amandine, Poyry, Tuija, Jones, Carolyn, Dudek, Kate, Patwardhan, Geetanjali, Meullenet, François, Oldham, Neil J., Walkinshaw, Malcolm D., Willis, Anne E., and Fischer, Peter M.
- Abstract
Eukaryotic translation initiation factor 4E (eIF4E) is considered as the corner stone in the cap-dependent translation initiation machinery. Its role is to recruit mRNA to the ribosome through recognition of the 50 - terminal mRNA cap structure (m7 GpppN, where G is guanosine, N is any nucleotide). eIF4E is implicated in cell transformation, tumourigenesis, and angiogenesis by facilitating translation of oncogenic mRNAs; it is thus regarded as an attractive anticancer drug target. We have used two approaches to design capbinding inhibitors of eIF4E by modifying the N7 -substituent of m7 GMP and replacing the phosphate group with isosteres such as squaramides, sulfonamides, and tetrazoles, as well as by structure-based virtual screening aimed at identifying non-nucleotide cap-binding antagonists. Phosphomimetic nucleotide derivatives and highly ranking virtual hits were evaluated in a series of in vitro and cell-based assays to identify the first non-nucleotide eIF4E cap-binding inhibitor with activities in cell-based assays, N-[(5,6-dihydro-6-oxo-1,3-dioxolo[4,5-g]quinolin-7-yl)methyl]-N0 -(2-methyl-propyl)-N-(phenylmethyl)thiourea (14), including down-regulation of oncogenic proteins and suppression of RNA incorporation into polysomes. Although we did not observe cellular activity with any of our modified m7 GMP phosphate isostere compounds, we obtained X-ray crystallography structures of three such compounds in complex with eIF4E, 50 -deoxy-50 -(1,2-dioxo-3-hydroxycyclobut-3-en-4-yl)amino-N7 -methyl-guanosine (4a), N7 -3-chlorobenzyl-50 -deoxy-50 -(1,2-dioxo-3-hydroxy-cyclobut-3-en-4-yl)amino-guanosine (4f), and N7 -benzyl-50 -deoxy-50 -(trifluoromethyl-sulfamoyl)guanosine (7a). Collectively, the data we present on structure-based design of eIF4E cap-binding inhibitors should facilitate the optimisation of such compounds as potential anticancer agents.
- Full Text
- View/download PDF
29. Pseudomonas aeruginosa quorum sensing systems as drug discovery targets: current position and future perspectives
- Author
-
Soukarieh, Fadi, Williams, Paul, Stocks, Michael John, Camara, Miguel, Soukarieh, Fadi, Williams, Paul, Stocks, Michael John, and Camara, Miguel
- Abstract
Antimicrobial resistance (AMR) is a serious threat to public health globally, manifested by the frequent emergence of multi-drug resistant pathogens that render current chemotherapy inadequate. Health organizations worldwide have recognized the severity of this crisis and implemented action plans to contain its adverse consequences and prolong the utility of conventional antibiotics. Hence, there is a pressing need for new classes of antibacterial agents with novel modes of action. Quorum sensing (QS), a communication system employed by bacterial populations to co-ordinate virulence gene expression, is a potential target that has been intensively investigated over the last decade. This Perspective will focus on recent advances in targeting the three main quorum sensing systems (las, rhl and pqs) of a major opportunistic human pathogen, Pseudomonas aeruginosa, and will specifically evaluate the medicinal chemistry strategies devised to develop QS inhibitors from a drug discovery perspective.
- Full Text
- View/download PDF
30. Lipophilic activated ester prodrug approach for drug delivery to the intestinal lymphatic system
- Author
-
Lee, Jong Bong, Zgair, Atheer, Malec, Jed, Kim, Tae Hwan, Kim, Min Gi, Ali, Joseph, Qin, Chaolong, Feng, Wanshan, Chiang, Manting, Gao, Xizhe, Voronin, Gregory, Garces, Aimie, Lau, Chun Long, Chan, Ting-Hoi, Hume, Amy, McIntosh, Tecashanell M., Soukarieh, Fadi, Al-Hayali, Mohammed, Cipolla, Elena, Collins, Hilary M., Heery, David M., Shin, Beom Soo, Yoo, Sun Dong, Kagan, Leonid, Stocks, Michael J., Bradshaw, Tracey D., Fischer, Peter M., Gershkovich, Pavel, Lee, Jong Bong, Zgair, Atheer, Malec, Jed, Kim, Tae Hwan, Kim, Min Gi, Ali, Joseph, Qin, Chaolong, Feng, Wanshan, Chiang, Manting, Gao, Xizhe, Voronin, Gregory, Garces, Aimie, Lau, Chun Long, Chan, Ting-Hoi, Hume, Amy, McIntosh, Tecashanell M., Soukarieh, Fadi, Al-Hayali, Mohammed, Cipolla, Elena, Collins, Hilary M., Heery, David M., Shin, Beom Soo, Yoo, Sun Dong, Kagan, Leonid, Stocks, Michael J., Bradshaw, Tracey D., Fischer, Peter M., and Gershkovich, Pavel
- Abstract
The intestinal lymphatic system plays an important role in the pathophysiology of multiple diseases including lymphomas, cancer metastasis, autoimmune diseases, and human immunodeficiency virus (HIV) infection. It is thus an important compartment for delivery of drugs in order to treat diseases associated with the lymphatic system. Lipophilic prodrug approaches have been used in the past to take advantage of the intestinal lymphatic transport processes to deliver drugs to the intestinal lymphatics. Most of the approaches previously adopted were based on very bulky prodrug moieties such as those mimicking triglycerides (TG). We now report a study in which a lipophilic prodrug approach was used to efficiently deliver bexarotene (BEX) and retinoic acid (RA) to the intestinal lymphatic system using activated ester prodrugs. A range of carboxylic ester prodrugs of BEX were designed and synthesised and all of the esters showed improved association with chylomicrons, which indicated an improved potential for delivery to the intestinal lymphatic system. The conversion rate of the prodrugs to BEX was the main determinant in delivery of BEX to the intestinal lymphatics, and activated ester prodrugs were prepared to enhance the conversion rate. As a result, an 4-(hydroxymethyl)-1,3-dioxol-2-one ester prodrug of BEX was able to increase the exposure of the mesenteric lymph nodes (MLNs) to BEX 17-fold compared to when BEX itself was administered. The activated ester prodrug approach was also applied to another drug, RA, where the exposure of the MLNs was increased 2.4-fold through the application of a similar cyclic activated prodrug. Synergism between BEX and RA was also demonstrated in vitro by cell growth inhibition assays using lymphoma cell lines. In conclusion, the activated ester prodrug approach results in efficient delivery of drugs to the intestinal lymphatic system, which could benefit patients affected by a large number of pathological conditions.
- Full Text
- View/download PDF
31. In silico and in vitro-guided identification of inhibitors of alkylquinolone-dependent quorum sensing in Pseudomonas aeruginosa
- Author
-
Soukarieh, Fadi, Oton, Eduard Vico, Dubern, Jean-Frédéric, Gomes, Janice, Halliday, Nigel, de Pilar Crespo, Maria, Ramírez-Prada, Jonathan, Insuasty, Braulio, Abonia, Rodrigo, Quiroga, Jairo, Heeb, Stephan, Williams, Paul, Stocks, Michael J., Cámara, Miguel, Soukarieh, Fadi, Oton, Eduard Vico, Dubern, Jean-Frédéric, Gomes, Janice, Halliday, Nigel, de Pilar Crespo, Maria, Ramírez-Prada, Jonathan, Insuasty, Braulio, Abonia, Rodrigo, Quiroga, Jairo, Heeb, Stephan, Williams, Paul, Stocks, Michael J., and Cámara, Miguel
- Abstract
Pseudomonas aeruginosa is a major opportunistic pathogen in cystic fibrosis, wound and nosocomial infections, posing a serious burden to public health, due to its antibiotic resistance. The P. aeruginosa Pseudomonas Quinolone System (pqs) quorum sensing system, driven by the activation of the transcriptional regulator, PqsR (MvfR) by alkylquinolone (AQ) signal molecules, is a key player in the regulation of virulence and a potential target for the development of novel antibacterial agents. In this study, we performed in silico docking analysis, coupled with screening using a P. aeruginosa mCTX::PpqsA-lux chromosomal promoter fusion, to identify a series of new PqsR antagonists. The hit compounds inhibited pyocyanin and alkylquinolone signal molecule production in P. aeruginosa PAO1-L and PA14 strains. The inhibitor Ia, which showed the highest activity in PA14, reduced biofilmformation in PAO1-L and PA14, increasing their sensitivity to tobramycin. Furthermore, the hepatic and plasma stabilities for these compounds were determined in both rat and human in vitro microsomal assays, to gain a further understanding of their therapeutic potential. This work has uncovered a new class of P. aeruginosa PqsR antagonists with potential for hit to lead optimisation in the search for quorum sensing inhibitors for future anti-infective drug discovery programs.
- Full Text
- View/download PDF
32. Design of nucleotide-mimetic and non-nucleotide inhibitors of the translation initiation factor eIF4E: synthesis, structural and functional characterisation
- Author
-
Soukarieh, Fadi, Nowicki, Matthew W., Bastide, Amandine, Poyry, Tuija, Jones, Carolyn, Dudek, Kate, Patwardhan, Geetanjali, Meullenet, François, Oldham, Neil J., Walkinshaw, Malcolm D., Willis, Anne E., Fischer, Peter M., Soukarieh, Fadi, Nowicki, Matthew W., Bastide, Amandine, Poyry, Tuija, Jones, Carolyn, Dudek, Kate, Patwardhan, Geetanjali, Meullenet, François, Oldham, Neil J., Walkinshaw, Malcolm D., Willis, Anne E., and Fischer, Peter M.
- Abstract
Eukaryotic translation initiation factor 4E (eIF4E) is considered as the corner stone in the cap-dependent translation initiation machinery. Its role is to recruit mRNA to the ribosome through recognition of the 50 - terminal mRNA cap structure (m7 GpppN, where G is guanosine, N is any nucleotide). eIF4E is implicated in cell transformation, tumourigenesis, and angiogenesis by facilitating translation of oncogenic mRNAs; it is thus regarded as an attractive anticancer drug target. We have used two approaches to design capbinding inhibitors of eIF4E by modifying the N7 -substituent of m7 GMP and replacing the phosphate group with isosteres such as squaramides, sulfonamides, and tetrazoles, as well as by structure-based virtual screening aimed at identifying non-nucleotide cap-binding antagonists. Phosphomimetic nucleotide derivatives and highly ranking virtual hits were evaluated in a series of in vitro and cell-based assays to identify the first non-nucleotide eIF4E cap-binding inhibitor with activities in cell-based assays, N-[(5,6-dihydro-6-oxo-1,3-dioxolo[4,5-g]quinolin-7-yl)methyl]-N0 -(2-methyl-propyl)-N-(phenylmethyl)thiourea (14), including down-regulation of oncogenic proteins and suppression of RNA incorporation into polysomes. Although we did not observe cellular activity with any of our modified m7 GMP phosphate isostere compounds, we obtained X-ray crystallography structures of three such compounds in complex with eIF4E, 50 -deoxy-50 -(1,2-dioxo-3-hydroxycyclobut-3-en-4-yl)amino-N7 -methyl-guanosine (4a), N7 -3-chlorobenzyl-50 -deoxy-50 -(1,2-dioxo-3-hydroxy-cyclobut-3-en-4-yl)amino-guanosine (4f), and N7 -benzyl-50 -deoxy-50 -(trifluoromethyl-sulfamoyl)guanosine (7a). Collectively, the data we present on structure-based design of eIF4E cap-binding inhibitors should facilitate the optimisation of such compounds as potential anticancer agents.
- Full Text
- View/download PDF
33. Lipophilic activated ester prodrug approach for drug delivery to the intestinal lymphatic system
- Author
-
Lee, Jong Bong, Zgair, Atheer, Malec, Jed, Kim, Tae Hwan, Kim, Min Gi, Ali, Joseph, Qin, Chaolong, Feng, Wanshan, Chiang, Manting, Gao, Xizhe, Voronin, Gregory, Garces, Aimie, Lau, Chun Long, Chan, Ting-Hoi, Hume, Amy, McIntosh, Tecashanell M., Soukarieh, Fadi, Al-Hayali, Mohammed, Cipolla, Elena, Collins, Hilary M., Heery, David M., Shin, Beom Soo, Yoo, Sun Dong, Kagan, Leonid, Stocks, Michael J., Bradshaw, Tracey D., Fischer, Peter M., Gershkovich, Pavel, Lee, Jong Bong, Zgair, Atheer, Malec, Jed, Kim, Tae Hwan, Kim, Min Gi, Ali, Joseph, Qin, Chaolong, Feng, Wanshan, Chiang, Manting, Gao, Xizhe, Voronin, Gregory, Garces, Aimie, Lau, Chun Long, Chan, Ting-Hoi, Hume, Amy, McIntosh, Tecashanell M., Soukarieh, Fadi, Al-Hayali, Mohammed, Cipolla, Elena, Collins, Hilary M., Heery, David M., Shin, Beom Soo, Yoo, Sun Dong, Kagan, Leonid, Stocks, Michael J., Bradshaw, Tracey D., Fischer, Peter M., and Gershkovich, Pavel
- Abstract
The intestinal lymphatic system plays an important role in the pathophysiology of multiple diseases including lymphomas, cancer metastasis, autoimmune diseases, and human immunodeficiency virus (HIV) infection. It is thus an important compartment for delivery of drugs in order to treat diseases associated with the lymphatic system. Lipophilic prodrug approaches have been used in the past to take advantage of the intestinal lymphatic transport processes to deliver drugs to the intestinal lymphatics. Most of the approaches previously adopted were based on very bulky prodrug moieties such as those mimicking triglycerides (TG). We now report a study in which a lipophilic prodrug approach was used to efficiently deliver bexarotene (BEX) and retinoic acid (RA) to the intestinal lymphatic system using activated ester prodrugs. A range of carboxylic ester prodrugs of BEX were designed and synthesised and all of the esters showed improved association with chylomicrons, which indicated an improved potential for delivery to the intestinal lymphatic system. The conversion rate of the prodrugs to BEX was the main determinant in delivery of BEX to the intestinal lymphatics, and activated ester prodrugs were prepared to enhance the conversion rate. As a result, an 4-(hydroxymethyl)-1,3-dioxol-2-one ester prodrug of BEX was able to increase the exposure of the mesenteric lymph nodes (MLNs) to BEX 17-fold compared to when BEX itself was administered. The activated ester prodrug approach was also applied to another drug, RA, where the exposure of the MLNs was increased 2.4-fold through the application of a similar cyclic activated prodrug. Synergism between BEX and RA was also demonstrated in vitro by cell growth inhibition assays using lymphoma cell lines. In conclusion, the activated ester prodrug approach results in efficient delivery of drugs to the intestinal lymphatic system, which could benefit patients affected by a large number of pathological conditions.
- Full Text
- View/download PDF
34. Pseudomonas aeruginosa quorum sensing systems as drug discovery targets: current position and future perspectives
- Author
-
Soukarieh, Fadi, Williams, Paul, Stocks, Michael John, Camara, Miguel, Soukarieh, Fadi, Williams, Paul, Stocks, Michael John, and Camara, Miguel
- Abstract
Antimicrobial resistance (AMR) is a serious threat to public health globally, manifested by the frequent emergence of multi-drug resistant pathogens that render current chemotherapy inadequate. Health organizations worldwide have recognized the severity of this crisis and implemented action plans to contain its adverse consequences and prolong the utility of conventional antibiotics. Hence, there is a pressing need for new classes of antibacterial agents with novel modes of action. Quorum sensing (QS), a communication system employed by bacterial populations to co-ordinate virulence gene expression, is a potential target that has been intensively investigated over the last decade. This Perspective will focus on recent advances in targeting the three main quorum sensing systems (las, rhl and pqs) of a major opportunistic human pathogen, Pseudomonas aeruginosa, and will specifically evaluate the medicinal chemistry strategies devised to develop QS inhibitors from a drug discovery perspective.
- Full Text
- View/download PDF
35. In silico and in vitro-guided identification of inhibitors of alkylquinolone-dependent quorum sensing in Pseudomonas aeruginosa
- Author
-
Soukarieh, Fadi, Oton, Eduard Vico, Dubern, Jean-Frédéric, Gomes, Janice, Halliday, Nigel, de Pilar Crespo, Maria, Ramírez-Prada, Jonathan, Insuasty, Braulio, Abonia, Rodrigo, Quiroga, Jairo, Heeb, Stephan, Williams, Paul, Stocks, Michael J., Cámara, Miguel, Soukarieh, Fadi, Oton, Eduard Vico, Dubern, Jean-Frédéric, Gomes, Janice, Halliday, Nigel, de Pilar Crespo, Maria, Ramírez-Prada, Jonathan, Insuasty, Braulio, Abonia, Rodrigo, Quiroga, Jairo, Heeb, Stephan, Williams, Paul, Stocks, Michael J., and Cámara, Miguel
- Abstract
Pseudomonas aeruginosa is a major opportunistic pathogen in cystic fibrosis, wound and nosocomial infections, posing a serious burden to public health, due to its antibiotic resistance. The P. aeruginosa Pseudomonas Quinolone System (pqs) quorum sensing system, driven by the activation of the transcriptional regulator, PqsR (MvfR) by alkylquinolone (AQ) signal molecules, is a key player in the regulation of virulence and a potential target for the development of novel antibacterial agents. In this study, we performed in silico docking analysis, coupled with screening using a P. aeruginosa mCTX::PpqsA-lux chromosomal promoter fusion, to identify a series of new PqsR antagonists. The hit compounds inhibited pyocyanin and alkylquinolone signal molecule production in P. aeruginosa PAO1-L and PA14 strains. The inhibitor Ia, which showed the highest activity in PA14, reduced biofilmformation in PAO1-L and PA14, increasing their sensitivity to tobramycin. Furthermore, the hepatic and plasma stabilities for these compounds were determined in both rat and human in vitro microsomal assays, to gain a further understanding of their therapeutic potential. This work has uncovered a new class of P. aeruginosa PqsR antagonists with potential for hit to lead optimisation in the search for quorum sensing inhibitors for future anti-infective drug discovery programs.
- Full Text
- View/download PDF
36. Design of nucleotide-mimetic and non-nucleotide inhibitors of the translation initiation factor eIF4E: synthesis, structural and functional characterisation
- Author
-
Soukarieh, Fadi, Nowicki, Matthew W., Bastide, Amandine, Poyry, Tuija, Jones, Carolyn, Dudek, Kate, Patwardhan, Geetanjali, Meullenet, François, Oldham, Neil J., Walkinshaw, Malcolm D., Willis, Anne E., Fischer, Peter M., Soukarieh, Fadi, Nowicki, Matthew W., Bastide, Amandine, Poyry, Tuija, Jones, Carolyn, Dudek, Kate, Patwardhan, Geetanjali, Meullenet, François, Oldham, Neil J., Walkinshaw, Malcolm D., Willis, Anne E., and Fischer, Peter M.
- Abstract
Eukaryotic translation initiation factor 4E (eIF4E) is considered as the corner stone in the cap-dependent translation initiation machinery. Its role is to recruit mRNA to the ribosome through recognition of the 50 - terminal mRNA cap structure (m7 GpppN, where G is guanosine, N is any nucleotide). eIF4E is implicated in cell transformation, tumourigenesis, and angiogenesis by facilitating translation of oncogenic mRNAs; it is thus regarded as an attractive anticancer drug target. We have used two approaches to design capbinding inhibitors of eIF4E by modifying the N7 -substituent of m7 GMP and replacing the phosphate group with isosteres such as squaramides, sulfonamides, and tetrazoles, as well as by structure-based virtual screening aimed at identifying non-nucleotide cap-binding antagonists. Phosphomimetic nucleotide derivatives and highly ranking virtual hits were evaluated in a series of in vitro and cell-based assays to identify the first non-nucleotide eIF4E cap-binding inhibitor with activities in cell-based assays, N-[(5,6-dihydro-6-oxo-1,3-dioxolo[4,5-g]quinolin-7-yl)methyl]-N0 -(2-methyl-propyl)-N-(phenylmethyl)thiourea (14), including down-regulation of oncogenic proteins and suppression of RNA incorporation into polysomes. Although we did not observe cellular activity with any of our modified m7 GMP phosphate isostere compounds, we obtained X-ray crystallography structures of three such compounds in complex with eIF4E, 50 -deoxy-50 -(1,2-dioxo-3-hydroxycyclobut-3-en-4-yl)amino-N7 -methyl-guanosine (4a), N7 -3-chlorobenzyl-50 -deoxy-50 -(1,2-dioxo-3-hydroxy-cyclobut-3-en-4-yl)amino-guanosine (4f), and N7 -benzyl-50 -deoxy-50 -(trifluoromethyl-sulfamoyl)guanosine (7a). Collectively, the data we present on structure-based design of eIF4E cap-binding inhibitors should facilitate the optimisation of such compounds as potential anticancer agents.
- Full Text
- View/download PDF
37. Lipophilic activated ester prodrug approach for drug delivery to the intestinal lymphatic system
- Author
-
Lee, Jong Bong, Zgair, Atheer, Malec, Jed, Kim, Tae Hwan, Kim, Min Gi, Ali, Joseph, Qin, Chaolong, Feng, Wanshan, Chiang, Manting, Gao, Xizhe, Voronin, Gregory, Garces, Aimie, Lau, Chun Long, Chan, Ting-Hoi, Hume, Amy, McIntosh, Tecashanell M., Soukarieh, Fadi, Al-Hayali, Mohammed, Cipolla, Elena, Collins, Hilary M., Heery, David M., Shin, Beom Soo, Yoo, Sun Dong, Kagan, Leonid, Stocks, Michael J., Bradshaw, Tracey D., Fischer, Peter M., Gershkovich, Pavel, Lee, Jong Bong, Zgair, Atheer, Malec, Jed, Kim, Tae Hwan, Kim, Min Gi, Ali, Joseph, Qin, Chaolong, Feng, Wanshan, Chiang, Manting, Gao, Xizhe, Voronin, Gregory, Garces, Aimie, Lau, Chun Long, Chan, Ting-Hoi, Hume, Amy, McIntosh, Tecashanell M., Soukarieh, Fadi, Al-Hayali, Mohammed, Cipolla, Elena, Collins, Hilary M., Heery, David M., Shin, Beom Soo, Yoo, Sun Dong, Kagan, Leonid, Stocks, Michael J., Bradshaw, Tracey D., Fischer, Peter M., and Gershkovich, Pavel
- Abstract
The intestinal lymphatic system plays an important role in the pathophysiology of multiple diseases including lymphomas, cancer metastasis, autoimmune diseases, and human immunodeficiency virus (HIV) infection. It is thus an important compartment for delivery of drugs in order to treat diseases associated with the lymphatic system. Lipophilic prodrug approaches have been used in the past to take advantage of the intestinal lymphatic transport processes to deliver drugs to the intestinal lymphatics. Most of the approaches previously adopted were based on very bulky prodrug moieties such as those mimicking triglycerides (TG). We now report a study in which a lipophilic prodrug approach was used to efficiently deliver bexarotene (BEX) and retinoic acid (RA) to the intestinal lymphatic system using activated ester prodrugs. A range of carboxylic ester prodrugs of BEX were designed and synthesised and all of the esters showed improved association with chylomicrons, which indicated an improved potential for delivery to the intestinal lymphatic system. The conversion rate of the prodrugs to BEX was the main determinant in delivery of BEX to the intestinal lymphatics, and activated ester prodrugs were prepared to enhance the conversion rate. As a result, an 4-(hydroxymethyl)-1,3-dioxol-2-one ester prodrug of BEX was able to increase the exposure of the mesenteric lymph nodes (MLNs) to BEX 17-fold compared to when BEX itself was administered. The activated ester prodrug approach was also applied to another drug, RA, where the exposure of the MLNs was increased 2.4-fold through the application of a similar cyclic activated prodrug. Synergism between BEX and RA was also demonstrated in vitro by cell growth inhibition assays using lymphoma cell lines. In conclusion, the activated ester prodrug approach results in efficient delivery of drugs to the intestinal lymphatic system, which could benefit patients affected by a large number of pathological conditions.
- Full Text
- View/download PDF
38. Pseudomonas aeruginosa quorum sensing systems as drug discovery targets: current position and future perspectives
- Author
-
Soukarieh, Fadi, Williams, Paul, Stocks, Michael John, Camara, Miguel, Soukarieh, Fadi, Williams, Paul, Stocks, Michael John, and Camara, Miguel
- Abstract
Antimicrobial resistance (AMR) is a serious threat to public health globally, manifested by the frequent emergence of multi-drug resistant pathogens that render current chemotherapy inadequate. Health organizations worldwide have recognized the severity of this crisis and implemented action plans to contain its adverse consequences and prolong the utility of conventional antibiotics. Hence, there is a pressing need for new classes of antibacterial agents with novel modes of action. Quorum sensing (QS), a communication system employed by bacterial populations to co-ordinate virulence gene expression, is a potential target that has been intensively investigated over the last decade. This Perspective will focus on recent advances in targeting the three main quorum sensing systems (las, rhl and pqs) of a major opportunistic human pathogen, Pseudomonas aeruginosa, and will specifically evaluate the medicinal chemistry strategies devised to develop QS inhibitors from a drug discovery perspective.
- Full Text
- View/download PDF
39. In silico and in vitro-guided identification of inhibitors of alkylquinolone-dependent quorum sensing in Pseudomonas aeruginosa
- Author
-
Soukarieh, Fadi, Oton, Eduard Vico, Dubern, Jean-Frédéric, Gomes, Janice, Halliday, Nigel, de Pilar Crespo, Maria, Ramírez-Prada, Jonathan, Insuasty, Braulio, Abonia, Rodrigo, Quiroga, Jairo, Heeb, Stephan, Williams, Paul, Stocks, Michael J., Cámara, Miguel, Soukarieh, Fadi, Oton, Eduard Vico, Dubern, Jean-Frédéric, Gomes, Janice, Halliday, Nigel, de Pilar Crespo, Maria, Ramírez-Prada, Jonathan, Insuasty, Braulio, Abonia, Rodrigo, Quiroga, Jairo, Heeb, Stephan, Williams, Paul, Stocks, Michael J., and Cámara, Miguel
- Abstract
Pseudomonas aeruginosa is a major opportunistic pathogen in cystic fibrosis, wound and nosocomial infections, posing a serious burden to public health, due to its antibiotic resistance. The P. aeruginosa Pseudomonas Quinolone System (pqs) quorum sensing system, driven by the activation of the transcriptional regulator, PqsR (MvfR) by alkylquinolone (AQ) signal molecules, is a key player in the regulation of virulence and a potential target for the development of novel antibacterial agents. In this study, we performed in silico docking analysis, coupled with screening using a P. aeruginosa mCTX::PpqsA-lux chromosomal promoter fusion, to identify a series of new PqsR antagonists. The hit compounds inhibited pyocyanin and alkylquinolone signal molecule production in P. aeruginosa PAO1-L and PA14 strains. The inhibitor Ia, which showed the highest activity in PA14, reduced biofilmformation in PAO1-L and PA14, increasing their sensitivity to tobramycin. Furthermore, the hepatic and plasma stabilities for these compounds were determined in both rat and human in vitro microsomal assays, to gain a further understanding of their therapeutic potential. This work has uncovered a new class of P. aeruginosa PqsR antagonists with potential for hit to lead optimisation in the search for quorum sensing inhibitors for future anti-infective drug discovery programs.
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- View/download PDF
40. Design of nucleotide-mimetic and non-nucleotide inhibitors of the translation initiation factor eIF4E: synthesis, structural and functional characterisation
- Author
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Soukarieh, Fadi, Nowicki, Matthew W., Bastide, Amandine, Poyry, Tuija, Jones, Carolyn, Dudek, Kate, Patwardhan, Geetanjali, Meullenet, François, Oldham, Neil J., Walkinshaw, Malcolm D., Willis, Anne E., Fischer, Peter M., Soukarieh, Fadi, Nowicki, Matthew W., Bastide, Amandine, Poyry, Tuija, Jones, Carolyn, Dudek, Kate, Patwardhan, Geetanjali, Meullenet, François, Oldham, Neil J., Walkinshaw, Malcolm D., Willis, Anne E., and Fischer, Peter M.
- Abstract
Eukaryotic translation initiation factor 4E (eIF4E) is considered as the corner stone in the cap-dependent translation initiation machinery. Its role is to recruit mRNA to the ribosome through recognition of the 50 - terminal mRNA cap structure (m7 GpppN, where G is guanosine, N is any nucleotide). eIF4E is implicated in cell transformation, tumourigenesis, and angiogenesis by facilitating translation of oncogenic mRNAs; it is thus regarded as an attractive anticancer drug target. We have used two approaches to design capbinding inhibitors of eIF4E by modifying the N7 -substituent of m7 GMP and replacing the phosphate group with isosteres such as squaramides, sulfonamides, and tetrazoles, as well as by structure-based virtual screening aimed at identifying non-nucleotide cap-binding antagonists. Phosphomimetic nucleotide derivatives and highly ranking virtual hits were evaluated in a series of in vitro and cell-based assays to identify the first non-nucleotide eIF4E cap-binding inhibitor with activities in cell-based assays, N-[(5,6-dihydro-6-oxo-1,3-dioxolo[4,5-g]quinolin-7-yl)methyl]-N0 -(2-methyl-propyl)-N-(phenylmethyl)thiourea (14), including down-regulation of oncogenic proteins and suppression of RNA incorporation into polysomes. Although we did not observe cellular activity with any of our modified m7 GMP phosphate isostere compounds, we obtained X-ray crystallography structures of three such compounds in complex with eIF4E, 50 -deoxy-50 -(1,2-dioxo-3-hydroxycyclobut-3-en-4-yl)amino-N7 -methyl-guanosine (4a), N7 -3-chlorobenzyl-50 -deoxy-50 -(1,2-dioxo-3-hydroxy-cyclobut-3-en-4-yl)amino-guanosine (4f), and N7 -benzyl-50 -deoxy-50 -(trifluoromethyl-sulfamoyl)guanosine (7a). Collectively, the data we present on structure-based design of eIF4E cap-binding inhibitors should facilitate the optimisation of such compounds as potential anticancer agents.
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41. Triblock copolymer micelles enhance solubility, permeability and activity of a quorum sensing inhibitor against Pseudomonas aeruginosa biofilms.
- Author
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Kasza K, Soukarieh F, Romero M, Hardie KR, Gurnani P, Cámara M, and Alexander C
- Abstract
Antimicrobial resistance is a threat to public health for which new treatments are urgently required. The capability of bacteria to form biofilms is of particular concern as it enables high bacterial tolerance to conventional therapies by reducing drug diffusion through the dense, exopolymeric biofilm matrix and the upregulation of antimicrobial resistance machinery. Quorum sensing (QS), a process where bacteria use diffusible chemical signals to coordinate group behaviour, has been shown to be closely interconnected with biofilm formation and bacterial virulence in many top priority pathogens including Pseudomonas aeruginosa . Inhibition of QS pathways therefore pose an attractive target for new therapeutics. We have recently reported a new series of pqs quorum sensing inhibitors (QSIs) that serve as potentiators for antibiotics in P. aeruginosa infections. The impact on biofilms of some reported QSIs was however hindered by their poor penetration through the bacterial biofilm, limiting the potential for clinical translation. In this study we developed a series of poly(β-amino ester) (PBAE) triblock copolymers and evaluated their ability to form micelles, encapsulate a QSI and enhance subsequent delivery to P. aeruginosa biofilms. We observed that the QSI could be released from polymer micelles, perturbing the pqs pathway in planktonic P. aeruginosa . In addition, one of the prepared polymer variants increased the QSIs efficacy, leading to an enhanced potentiation of ciprofloxacin (CIP) action and therefore improved reduction in biofilm viability, compared to the non-encapsulated QSI. Thus, we demonstrate QSI encapsulation in polymeric particles can enhance its efficacy through improved biofilm penetration., Competing Interests: We declare no conflicts of interest., (This journal is © The Royal Society of Chemistry.)
- Published
- 2024
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42. Design, Synthesis, and Evaluation of New 1 H -Benzo[ d ]imidazole Based PqsR Inhibitors as Adjuvant Therapy for Pseudomonas aeruginosa Infections.
- Author
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Soukarieh F, Mashabi A, Richardson W, Oton EV, Romero M, Dubern JF, Robertson SN, Lucanto S, Markham-Lee Z, Sou T, Kukavica-Ibrulj I, Levesque RC, Bergstrom CAS, Halliday N, Kellam B, Emsley J, Heeb S, Williams P, Stocks MJ, and Cámara M
- Subjects
- Humans, Quorum Sensing, Biofilms, Anti-Bacterial Agents pharmacology, Anti-Bacterial Agents therapeutic use, Anti-Bacterial Agents metabolism, Imidazoles pharmacology, Imidazoles therapeutic use, Imidazoles metabolism, Pseudomonas aeruginosa metabolism, Bacterial Proteins, Virulence Factors, Pseudomonas Infections drug therapy, Pseudomonas Infections microbiology, Quinolones pharmacology
- Abstract
Pseudomonas aeruginosa is one of the top priority pathogens that requires immediate attention according to the World Health Organisation (WHO). Due to the alarming shortage of novel antimicrobials, targeting quorum sensing (QS), a bacterial cell to cell signaling system controlling virulence, has emerged as a promising approach as an antibiotic adjuvant therapy. Interference with the pqs system, one of three QS systems in P. aeruginosa , results in reduction of bacterial virulence gene expression and biofilm maturation. Herein, we report a hit to lead process to fine-tune the potency of our previously reported inhibitor 1 (IC
50 3.2 μM in P. aeruginosa PAO1-L), which led to the discovery of 2-(4-(3-((6-chloro-1-isopropyl-1 H -benzo[ d ]imidazol-2-yl)amino)-2-hydroxypropoxy)phenyl)acetonitrile ( 6f ) as a potent PqsR antagonist. Compound 6f inhibited the PqsR-controlled PpqsA - lux transcriptional reporter fusion in P. aeruginosa at low submicromolar concentrations. Moreover, 6f showed improved efficacy against P. aeruginosa CF isolates with significant inhibition of pyocyanin, 2-alkyl-4(1 H )-quinolones production.- Published
- 2024
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- View/download PDF
43. Design and Evaluation of New Quinazolin-4(3 H )-one Derived PqsR Antagonists as Quorum Sensing Quenchers in Pseudomonas aeruginosa .
- Author
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Soukarieh F, Mashabi A, Richardson W, Oton EV, Romero M, Roberston SN, Grossman S, Sou T, Liu R, Halliday N, Kukavica-Ibrulj I, Levesque RC, Bergstrom CAS, Kellam B, Emsley J, Heeb S, Williams P, Stocks MJ, and Cámara M
- Subjects
- Bacterial Proteins metabolism, Biofilms, Gene Expression Regulation, Bacterial, Pseudomonas aeruginosa metabolism, Quorum Sensing
- Abstract
P. aeruginosa (PA) continues to pose a threat to global public health due to its high levels of antimicrobial resistance (AMR). The ongoing AMR crisis has led to an alarming shortage of effective treatments for resistant microbes, and hence there is a pressing demand for the development of novel antimicrobial interventions. The potential use of antivirulence therapeutics to tackle bacterial infections has attracted considerable attention over the past decades as they hamper the pathogenicity of target microbes with reduced selective pressure, minimizing the emergence of resistance. One such approach is to interfere with the PA pqs quorum sensing system which upon the interaction of PqsR, a Lys-R type transcriptional regulator, with its cognate signal molecules 4-hydroxy-2-heptylquinoline (HHQ) and 2-heptyl-3-hydroxy-4-quinolone (PQS), governs multiple virulence traits and host-microbe interactions. In this study, we report the hit identification and optimization of PqsR antagonists using virtual screening coupled with whole cell assay validation. The optimized hit compound 61 (( R )-2-(4-(3-(6-chloro-4-oxoquinazolin-3(4 H )-yl)-2-hydroxypropoxy)phenyl)acetonitrile) was found to inhibit the expression of the PA P
pqsA promoter controlled by PqsR with an IC50 of 1 μM. Using isothermal titration calorimetry, a Kd of 10 nM for the PqsR ligand binding domain (PqsRLBD ) was determined for 61. Furthermore, the crystal structure of 61 with PqsRLBD was attained with a resolution of 2.65 Å. Compound 61 significantly reduced levels of pyocyanin, PQS, and HHQ in PAO1-L, PA14 lab strains and PAK6085 clinical isolate. Furthermore, this compound potentiated the effect of ciprofloxacin in early stages of biofilm treatment and in Galleria mellonella infected with PA. Altogether, this data shows 61 as a potent PqsR inhibitor with potential for hit to lead optimization toward the identification of a PA QS inhibitor which can be advanced into preclinical development.- Published
- 2021
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44. In Silico and in Vitro-Guided Identification of Inhibitors of Alkylquinolone-Dependent Quorum Sensing in Pseudomonas aeruginosa.
- Author
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Soukarieh F, Vico Oton E, Dubern JF, Gomes J, Halliday N, de Pilar Crespo M, Ramírez-Prada J, Insuasty B, Abonia R, Quiroga J, Heeb S, Williams P, Stocks MJ, and Cámara M
- Subjects
- Transcription Factors genetics, Transcription Factors metabolism, Anti-Bacterial Agents chemistry, Biofilms, Molecular Docking Simulation, Pseudomonas aeruginosa physiology, Quinolones metabolism, Quorum Sensing drug effects, Transcription Factors antagonists & inhibitors
- Abstract
Pseudomonas aeruginosa is a major opportunistic pathogen in cystic fibrosis, wound and nosocomial infections, posing a serious burden to public health, due to its antibiotic resistance. The P. aeruginosa Pseudomonas Quinolone System ( pqs ) quorum sensing system, driven by the activation of the transcriptional regulator, PqsR (MvfR) by alkylquinolone (AQ) signal molecules, is a key player in the regulation of virulence and a potential target for the development of novel antibacterial agents. In this study, we performed in silico docking analysis, coupled with screening using a P. aeruginosa mCTX::P
pqsA - lux chromosomal promoter fusion, to identify a series of new PqsR antagonists. The hit compounds inhibited pyocyanin and alkylquinolone signal molecule production in P. aeruginosa PAO1-L and PA14 strains. The inhibitor Ia , which showed the highest activity in PA14, reduced biofilm formation in PAO1-L and PA14, increasing their sensitivity to tobramycin. Furthermore, the hepatic and plasma stabilities for these compounds were determined in both rat and human in vitro microsomal assays, to gain a further understanding of their therapeutic potential. This work has uncovered a new class of P. aeruginosa PqsR antagonists with potential for hit to lead optimisation in the search for quorum sensing inhibitors for future anti-infective drug discovery programs., Competing Interests: The authors declare no conflicts of interest.- Published
- 2018
- Full Text
- View/download PDF
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