Phage-Choline Kinase Inhibitor Combination to Control Pseudomonas aeruginosa: A Promising Combo

2021 ◽  
Vol 21 ◽  
Author(s):  
Moad Khalifa ◽  
Ling Ling Few ◽  
Wei Cun See Too
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Choline Kinase ◽  
Gram Negative Bacteria ◽  
The Novel ◽  
Opportunistic Pathogens ◽  
Phage Cocktail ◽  
Wonder Drug ◽  
Inhibitor Combination

Background: : Pseudomonas aeruginosa is one of the most prevalent opportunistic pathogens in humans that has thrived and proved to be difficult to control in this “post-antibiotic era.” Antibiotic alternatives are necessary for fighting against this resilient bacterium. Even though phages might not be “the wonder drug” that solves everything, they still provide a viable option to combat P. aeruginosa and curb the threat it imposes. Main findings: : The combination of antibiotics with phages, however, poses a propitious treatment option for P. aeruginosa. Choline kinase (ChoK) is the enzyme that synthesizes phosphorylcholine subsequently incorporated into lipopolysaccharide located at the outer membrane of gram-negative bacteria. Recently, inhibition of ChoKs has been proposed as a promising antibacterial strategy. Successful docking of Hemicholinium-3, a choline kinase inhibitor, to the model structure of P. aeruginosa ChoK also supports the use of this inhibitor or its derivatives to inhibit the growth of this microorganism. Conclusion: : Therefore, the combination of the novel antimicrobial “choline kinase inhibitors (ChoKIs)” with a phage cocktail or synthetic phages as a potential treatment for P. aeruginosa infection has been proposed.

Novel Tyrosine Kinase Inhibitors Trigger Drug Sensitivity of Primary CLL Cells by Controlling Glucosylation of Ceramides

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3905-3905
Author(s):  
Janine Schwamb ◽  
Valeska Feldhaus ◽  
Michael Baumann ◽  
Michaela Patz ◽  
Susanne Brodesser ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Conflicts Of Interest ◽  
Treatment Options ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Published Data ◽  
The Novel ◽  
Apoptosis Resistance

Abstract Abstract 3905 Background: Apoptosis resistance of chronic lymphocytic leukemia (CLL) cells is mediated by several pro-survival stimuli. In particular, engagement of the B-cell receptor (BCR), CD40-CD40 ligand (CD40L) interaction or stimulation by interleukin-(IL)-4 were identified as major factors to regulate chemoresistance. Sphingolipids are known to be involved in several metabolic pathways involved in chemoresitance. Therefore, we focused on ceramide as pro-apoptotic molecule and its counterpart glucosylceramide, which rather contributes to proliferation and survival. Methods and Results: Applying liquid chromatography electrospray ionization tandem mass spectrometry, we revealed a significant decrease of pro-apoptotic ceramide in BCR/IL-4/CD40L-stimulated primary CLL cells compared to untreated controls (p=0.0258, p=0.0478, p=0.0114). Anti-apoptotic glucosylceramide levels were significantly increased after BCR cross-linking (p=0.0435) while other stimuli caused no relevant change in glucosylceramide expression. We identified BCR engagement to catalyze the crucial modification of ceramide to glucosylceramide via the enzyme UDP-glucose ceramide glucosyltransferase (UGCG) (p=0.0001). Besides specific UGCG inhibitors, we could show for the first time that IgM-mediated UGCG expression was significantly inhibited by the novel and highly effective PI3Kδ and BTK inhibitors CAL-101 and PCI-32765, which were able to revert IgM-induced apoptosis resistance of CLL cells. Recently published data revealed sphingolipids to be essential for mediation of apoptosis via mitochondria. Therefore, we chose ABT-737 – a well-known and also mitochondria-targeting drug – as candidate partner for PI3Kδ and BTK inhibition. When combining each tyrosine kinase inhibitor with ABT-737, a synergistic apoptotic effect could be documented, even under protection by BCR stimulation. Conclusion: In summary, we could demonstrate that sphingolipids are critically involved in CLL pathogenesis. UGCG could be identified as drugable target by the novel kinase inhibitors CAL-101 and PCI-32765 resulting in even synergistic apoptosis following additional application of ABT-737. Sphingolipids seem to offer further targets providing novel treatment options in CLL. C.M.W. and L.P.F. contributed equally to this work. Disclosures: No relevant conflicts of interest to declare.

The Kinase Inhibitor TKI258 Is Active Against the Novel CUX1-FGFR1 Fusion Detected In a Patient with T-Lymphoblastic Leukemia/Lymphoma and t(7;8)(q22;p11)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2715-2715
Author(s):  
Bartosz Wasag ◽  
Els Lierman ◽  
Peter Meeus ◽  
Jan Cools ◽  
Peter Vandenberghe
Keyword(s):  
Cell Line ◽  
Western Blotting ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Antiproliferative Effect ◽  
Fusion Partner ◽  
The Novel

Abstract Abstract 2715 The 8p11 myeloproliferative syndrome (EMS) is an aggressive, atypical stem cell disorder associated with chromosome translocations that constitutively activate FGFR1 by fusion to diverse partner genes. Here, we describe a case with a clinical and hematological diagnosis of T-lymphoblastic leukemia/lymphoma and with a t(7;8)(q22;p11) on cytogenetic analysis. We identified the fusion partner involved and characterized this translocation functionally in vitro using the interleukin 3 (IL3) dependent Ba/F3 cell line. The translocation was analyzed in more detail by FISH using FGFR1 flanking probes. We could confirm the 8p11 breakpoint and 7q as the partner chromosome. Using 5'-RACE CUX1 (7q22) was identified as the fusion partner of FGFR1 in this patient with T-lymphoblastic leukemia/lymphoma. CUX1 is a homeobox family DNA binding protein not previously described as a fusion partner in hematological malignancies. To evaluate the transforming potential of this novel fusion, the CUX1-FGFR1 fusion was cloned and used to transform Ba/F3 cells. CUX1-FGFR1 expressing Ba/F3 cells displayed IL3 independent proliferation thus demonstrating the oncogenic character of this fusion protein. Western blotting of the transformed Ba/F3 cells showed activation of FGFR1 as well as its downstream target STAT5. Treatment of the CUX1-FGFR1 expressing Ba/F3 cells with the kinase inhibitors PKC412 and TKI258 significantly inhibited cell growth with an IC50 of 483 and 489 nM respectively. With western blotting a direct effect of both inhibitors on FGFR1 kinase activity as well as on different downstream effectors was proven. Furthermore using an annexinV/propidium iodide-based apoptosis assay, we could show that PKC412 and TKI258 both induced apoptosis followed by cell death in inhibitor treated CUX1-FGFR1 transformed Ba/F3 cells. The antiproliferative effect of the inhibitors could be rescued by addition of IL3 for the TKI258 treated but not for PKC412 treated CUX1-FGFR1 expressing cells. This observation indicates a selective action of TKI258 on FGFR1 signaling at the concentrations used. In contrast, for PKC412 non-specific cytotoxicity is also contributing to the antiproliferative effect. In summary, we identified a novel CUX1-FGFR1 fusion in a case with EMS and a novel t(7;8)(q22;p11), and demonstrated the oncogenic potential of CUX1-FGFR1 in the Ba/F3 cell line. This new fusion partner CUX1 contains a potential coiled coil domain that can explain the observed constitutive FGFR1 activation, as has been elaborately demonstrated for other oncogenic kinase fusions. The in vitro data presented here using the inhibitor TKI258 support the use of this compound for the treatment of the novel CUX1-FGFR1 fusion as well as other constitutively active FGFR1 fusion proteins. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Pseudomonas aeruginosa induces p38MAP kinase-dependent IL-6 and CXCL8 release from bronchial epithelial cells via a Syk kinase pathway

PLoS ONE ◽  
2021 ◽  
Vol 16 (2) ◽  
pp. e0246050
Author(s):  
Matthew S. Coates ◽  
Eric W. F. W. Alton ◽  
Garth W. Rapeport ◽  
Jane C. Davies ◽  
Kazuhiro Ito
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Epithelial Cells ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Inflammatory Responses ◽  
Syk Kinase ◽  
Low Concentrations ◽  
Mitogen Activated Protein ◽  
Syk Inhibitor

Pseudomonas aeruginosa (Pa) infection is a major cause of airway inflammation in immunocompromised and cystic fibrosis (CF) patients. Mitogen-activated protein (MAP) and tyrosine kinases are integral to inflammatory responses and are therefore potential targets for novel anti-inflammatory therapies. We have determined the involvement of specific kinases in Pa-induced inflammation. The effects of kinase inhibitors against p38MAPK, MEK 1/2, JNK 1/2, Syk or c-Src, a combination of a p38MAPK with Syk inhibitor, or a novel narrow spectrum kinase inhibitor (NSKI), were evaluated against the release of the proinflammatory cytokine/chemokine, IL-6 and CXCL8 from BEAS-2B and CFBE41o- epithelial cells by Pa. Effects of a Syk inhibitor against phosphorylation of the MAPKs were also evaluated. IL-6 and CXCL8 release by Pa were significantly inhibited by p38MAPK and Syk inhibitors (p<0.05). Phosphorylation of HSP27, but not ERK or JNK, was significantly inhibited by Syk kinase inhibition. A combination of p38MAPK and Syk inhibitors showed synergy against IL-6 and CXCL8 induction and an NSKI completely inhibited IL-6 and CXCL8 at low concentrations. Pa-induced inflammation is dependent on p38MAPK primarily, and Syk partially, which is upstream of p38MAPK. The NSKI suggests that inhibiting specific combinations of kinases is a potent potential therapy for Pa-induced inflammation.

scholarly journals Gram-Positive and Gram-Negative Bacteria Do Not Trigger Monocytic Cytokine Production through Similar Intracellular Pathways

2001 ◽  
Vol 69 (7) ◽  
pp. 4590-4599 ◽  
Author(s):  
Lila Rabehi ◽  
Théano Irinopoulou ◽  
Béatrice Cholley ◽  
Nicole Haeffner-Cavaillon ◽  
Marie-Paule Carreno
Keyword(s):  
Kinase Inhibitors ◽  
Cytokine Production ◽  
Kinase Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Gram Negative Bacteria ◽  
Gram Positive ◽  
Necrosis Factor Alpha ◽  
Gram Negative ◽  
Tnf Α ◽  
P38 Pathway

ABSTRACT Toll-like receptors (TLRs) are involved in human monocyte activation by lipopolysaccharide (LPS) and Staphylococcus aureus Cowan (SAC), suggesting that gram-positive and gram-negative bacteria may trigger similar intracellular events. Treatment with specific kinase inhibitors prior to cell stimulation dramatically decreased LPS-induced cytokine production. Blocking of the p38 pathway prior to LPS stimulation decreased interleukin-1α (IL-1α), IL-1ra, and tumor necrosis factor alpha (TNF-α) production, whereas blocking of the ERK1/2 pathways inhibited IL-1α, IL-1β, and IL-1ra but not TNF-α production. When cells were stimulated by SAC, inhibition of the p38 pathway did not affect cytokine production, whereas only IL-1α production was decreased in the presence of ERK kinase inhibitor. We also demonstrated that although LPS and SAC have been shown to bind to CD14 before transmitting signals to TLR4 and TLR2, respectively, internalization of CD14 occurred only in monocytes triggered by LPS. Pretreatment of the cells with SB203580, U0126, or a mixture of both inhibitors did not affect internalization of CD14. Altogether, these results suggest that TLR2 signaling does not involve p38 mitogen-activated protein kinase signaling pathways, indicating that divergent pathways are triggered by gram-positive and gram-negative bacteria, thereby inducing cytokine production.

scholarly journals The novel choline kinase inhibitor ICL-CCIC-0019 reprograms cellular metabolism and inhibits cancer cell growth

Oncotarget ◽  
2016 ◽  
Vol 7 (24) ◽  
pp. 37103-37120 ◽  
Author(s):  
Sebastian Trousil ◽  
Maciej Kaliszczak ◽  
Zachary Schug ◽  
Quang-De Nguyen ◽  
Giampaolo Tomasi ◽  
...  
Keyword(s):  
Cell Growth ◽  
Cancer Cell ◽  
Kinase Inhibitor ◽  
Cellular Metabolism ◽  
Choline Kinase ◽  
The Novel ◽  
Cancer Cell Growth

scholarly journals Crowdsourced mapping extends the target space of kinase inhibitors

2020 ◽  
Author(s):  
Anna Cichonska ◽  
Balaguru Ravikumar ◽  
Robert J Allaway ◽  
Sungjoon Park ◽  
Fangping Wan ◽  
...  
Keyword(s):  
Small Molecules ◽  
Kinase Activity ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Predictive Accuracy ◽  
Target Space ◽  
Gradient Boosting ◽  
The Novel ◽  
Model Predictions ◽  
Intensive Search

AbstractDespite decades of intensive search for compounds that modulate the activity of particular targets, there are currently small-molecules available only for a small proportion of the human proteome. Effective approaches are therefore required to map the massive space of unexplored compound-target interactions for novel and potent activities. Here, we carried out a crowdsourced benchmarking of predictive models for kinase inhibitor potencies across multiple kinase families using unpublished bioactivity data. The top-performing predictions were based on kernel learning, gradient boosting and deep learning, and their ensemble resulted in predictive accuracy exceeding that of kinase activity assays. We then made new experiments based on the model predictions, which further improved the accuracy of experimental mapping efforts and identified unexpected potencies even for under-studied kinases. The open-source algorithms together with the novel bioactivities between 95 compounds and 295 kinases provide a resource for benchmarking new prediction algorithms and for extending the druggable kinome.

Confocal and SEM imaging to demonstrate food pathogen- biofilm biocontrol by pyocyanin from Pseudomonas aeruginosa BTRY1

2016 ◽  
Vol 6 (01) ◽  
pp. 5218
Author(s):  
Laxmi Mohandas ◽  
Anju T. R. ◽  
Sarita G. Bhat*
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Biofilm Formation ◽  
Laser Scanning ◽  
Laser Scanning Microscopy ◽  
Confocal Laser ◽  
Antibiofilm Activity ◽  
Opportunistic Pathogens ◽  
Redox Active ◽  
Sem Imaging ◽  
The Impact

An assortment of redox-active phenazine compounds like pyocyanin with their characteristic blue-green colour are synthesized by Pseudomonas aeruginosa, Gram-negative opportunistic pathogens, which are also considered one of the most commercially valuable microorganisms. In this study, pyocyanin from Pseudomonas aeruginosa BTRY1 from food sample was assessed for its antibiofilm activity by micro titer plate assay against strong biofilm producers belonging to the genera Bacillus, Staphylococcus, Brevibacterium and Micrococcus. Pyocyanin inhibited biofilm activity in very minute concentrations. This was also confirmed by Scanning Electron Microscopy (SEM) and Confocal Laser Scanning Microscopy (CLSM). Both SEM and CLSM helped to visualize the biocontrol of biofilm formation by eight pathogens. The imaging and quantification by CLSM also established the impact of pyocyanin on biofilm-biocontrol mainly in the food industry.

scholarly journals Thrombotic microangiopathy in dasatinib-treated patients with chronic myeloid leukemia

2019 ◽  
Vol 4 (1-2) ◽  
pp. 41-45 ◽  
Author(s):  
Takeo Koshida ◽  
Sylvia Wu ◽  
Hitoshi Suzuki ◽  
Rimda Wanchoo ◽  
Vanesa Bijol ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Tyrosine Kinase Inhibitors ◽  
Thrombotic Microangiopathy ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kidney Biopsy ◽  
Kinase Inhibitor ◽  
Target Effect

Dasatinib is the second-generation tyrosine kinase inhibitor used in the treatment of chronic myeloid leukemia. Proteinuria has been reported with this agent. We describe two kidney biopsy–proven cases of dasatinib-induced thrombotic microangiopathy that responded to stoppage of dasatinib and using an alternate tyrosine kinase inhibitor. Certain specific tyrosine kinase inhibitors lead to endothelial injury and renal-limited thrombotic microangiopathy. Hematologists and nephrologists need to be familiar with this off-target effect of dasatinib.

scholarly journals Computational evaluation of potent 2-(1H-imidazol-2-yl) pyridine derivatives as potential V600E-BRAF inhibitors

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Abdullahi Bello Umar ◽  
Adamu Uzairu ◽  
Gideon Adamu Shallangwa ◽  
Sani Uba
Keyword(s):  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Acquired Resistance ◽  
Docking Studies ◽  
Major Protein ◽  
Pharmacological Properties ◽  
Braf Inhibitors ◽  
Protein Target ◽  
Computational Evaluation ◽  
Better Than

Abstract Background V600E-BRAF is a major protein target involved in various types of human cancers. However, the acquired resistance of the V600E-BRAF kinase to the vemurafenib and the side effects of other identified drugs initiate the search for efficient inhibitors. In the current paper, virtual docking screening combined with drug likeness and ADMET properties predictions were jointly applied to evaluate potent 2-(1H-imidazol-2-yl) pyridines as V600E-BRAF kinase inhibitors. Results Most of the studied compounds showed better docking scores and favorable interactions with theiV600E-BRAF target. Among the screened compounds, the two most potent (14 and 30) with good rerank scores (−124.079 and − 122.290) emerged as the most effective, and potent V600E-BRAF kinase inhibitors which performed better than vemurafenib (−116.174), an approved V600E-BRAF kinase inhibitor. Thus, the docking studies exhibited that these compounds have shown competing inhibition of V600E-BRAF kinase with vemurafenib at the active site and revealed better pharmacological properties based on Lipinski’s and Veber’s drug-likeness rules for oral bioavailability and ADMET properties. Conclusion The docking result, drug-likeness rules, and ADMET parameters identified compounds (14 and 30) as the best hits against V600E-BRAF kinase with better pharmacological properties. This suggests that these compounds may be developed as potent V600E-BRAF inhibitors.

Sign in / Sign up

Export Citation Format

Share Document