The resistance development is an increasing global health risk that needs innovative solutions. Repurposing drugs to serve as anti-virulence agents is suggested as an advantageous strategy to ...diminish bacterial resistance development. Bacterial virulence is controlled by quorum sensing (QS) system that orchestrates the expression of biofilm formation, motility, and virulence factors production as enzymes and virulent pigments. Interfering with QS could lead to bacterial virulence mitigation without affecting bacterial growth that does not result in bacterial resistance development. This study investigated the probable anti-virulence and anti-QS activities of α-adrenoreceptor blocker doxazosin against
Proteus mirabilis
and
Pseudomonas aeruginosa
. Besides in silico study, in vitro and in vivo investigations were conducted to assess the doxazosin anti-virulence actions. Doxazosin significantly diminished the biofilm formation and release of QS-controlled
Chromobacterium violaceum
pigment and virulence factors in
P. aeruginosa
and
P. mirabilis
, and downregulated the QS encoding genes in
P. aeruginosa
. Virtually, doxazosin interfered with QS proteins, and in vivo protected mice against
P. mirabilis
and
P. aeruginosa
. The role of the membranal sensors as QseC and PmrA was recognized in enhancing the Gram-negative virulence. Doxazosin downregulated the membranal sensors PmR and QseC encoding genes and could in silico interfere with them. In conclusion, this study preliminary documents the probable anti-QS and anti-virulence activities of doxazosin, which indicate its possible application as an alternative or in addition to antibiotics. However, extended toxicological and pharmacological investigations are essential to approve the feasible clinical application of doxazosin as novel efficient anti-virulence agent.
Key points
• Anti-hypertensive doxazosin acquires anti-quorum sensing activities
• Doxazosin diminishes the virulence of Proteus mirabilis and Pseudomonas aeruginosa
• Doxazosin could dimmish the bacterial espionage
We designed and synthesised novel quinazolinone tethered phenyl urea derivatives (6a-p) that triple target the double mutant EGFR
L858R/T790M
, COX-2, and 15-LOX. Compounds (6e, 6d, 6j, 6m, and 6n) ...not only had low micromolar IC50 inhibitory activities against the three targets, but they also showed good selectivity for COX-2 over COX-1 and for EGFR
L858R/T790M
over wild-type EGFR. Except for 6e and 6n, all of the tested compounds inhibited the NO production significantly more potently than celecoxib, diclofenac, and indomethacin. Compounds 6i and 6k reduced ROS levels more effectively than celecoxib and diclofenac. In terms of inhibiting TNF-α production, 6o-treated cells showed TNF-α level, which is ∼10 times lower than celecoxib. Furthermore, 6e and 6j had the highest anticancer activity against the breast cancer cell line BT-459 with growth inhibition percentages of 67.14 and 70.07%, respectively. Docking studies confirm their favoured binding affinity. The proposed compounds could be promising multi-targeted leads.
The development of bacterial resistance to antibiotics is an increasing public health issue that worsens with the formation of biofilms. Quorum sensing (QS) orchestrates the bacterial virulence and ...controls the formation of biofilm. Targeting bacterial virulence is promising approach to overcome the resistance increment to antibiotics. In a previous detailed in silico study, the anti-QS activities of twenty-two β-adrenoreceptor blockers were screened supposing atenolol as a promising candidate. The current study aims to evaluate the anti-QS, anti-biofilm and anti-virulence activities of the β-adrenoreceptor blocker atenolol against Gram-negative bacteria Serratia marcescens, Pseudomonas aeruginosa, and Proteus mirabilis. An in silico study was conducted to evaluate the binding affinity of atenolol to S. marcescens SmaR QS receptor, P. aeruginosa QscR QS receptor, and P. mirabilis MrpH adhesin. The atenolol anti-virulence activity was evaluated against the tested strains in vitro and in vivo. The present finding shows considerable ability of atenolol to compete with QS proteins and significantly downregulated the expression of QS- and virulence-encoding genes. Atenolol showed significant reduction in the tested bacterial biofilm formation, virulence enzyme production, and motility. Furthermore, atenolol significantly diminished the bacterial capacity for killing and protected mice. In conclusion, atenolol has potential anti-QS and anti-virulence activities against S. marcescens, P. aeruginosa, and P. mirabilis and can be used as an adjuvant in treatment of aggressive bacterial infections.
Background: Acute kidney injury (AKI) induced by renal ischemia-reperfusion injury (RIRI) is associated with a high incidence of mortality. Existing therapies are mainly supportive, with no available ...nephroprotective agent. The purpose of this study is to examine the potential protective effect of Agathis robusta Bark Extract (ARBE) in RIRI. Methods: The chemical composition of ARBE was examined by LC-ESI-MS/MS. Network pharmacology was utilized to identify the RIRI molecular targets that could be aimed at by the identified major components of ARBE. Experimentally validated protein–protein interactions (PPIs) and compound-target networks were constructed using the STRING database and Cytoscape software. Molecular docking studies were employed to assess the interaction of the most relevant ARBE compounds with the hub RIRI-related targets. Furthermore, ARBE was tested in a rat model of RIRI. Results: The phytochemical analysis identified 95 components in ARBE, 37 of which were majors. Network analysis identified 312 molecular targets of RIRI that were associated with ARBE major compounds. Of these 312, the top targets in the experimentally validated PPI network were HSP90, EGFR, and P53. The most relevant compounds based on their peak area and network degree value included narcissoside, isorhamnetin-3-O-glucoside, and syringetin-3-O-glucoside, among others. Docking studies of the most relevant compounds revealed significant interactions with the top RIRI-related targets. In the in vivo RIRI experiments, pretreatment of ARBE improved kidney function and structural changes. ARBE reduced the renal expression of p-NfkB and cleaved caspase-3 by downregulating HSP90 and P53 in rats exposed to RIRI. Conclusion: Taken together, this study revealed the chemical composition of ARBE, depicted the interrelationship of the bioactive ingredients of ARBE with the RIRI-related molecular targets, and validated a nephroprotective effect of ARBE in RIRI.
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2), the causative agent of Coronavirus Disease 2019 (COVID-19), has seriously threatened global health. Alongside the approved vaccines, the ...discovery of prospective anti-COVID-19 drugs has been progressively targeted. Essential oils (EOs) provide a rich source of compounds with valuable antiviral activities that may contribute as effective agents against COVID-19. In this study, the EO of
bark was investigated for its chemical composition and its antiviral activity against SARS-CoV2. Overall, 26 constituents were identified by gas chromatography-mass spectrometry (GC-MS) analysis.
-Pinene, tricyclene,
-terpineol, limonene,
-camphene,
-pinocarveol,
-phellandren-8-ol, L-
-pinene and borneol were the major components. In silico docking of these constituents against viral key enzymes, spike receptor-binding domain (RBD), main protease (Mpro) and RNA-dependent RNA polymerase (RdRp), using Molecular Operating Environment (MOE) software revealed good binding affinities of the components to the active site of the selected targets, especially, the RBD. In Vitro antiviral MTT and cytopathic effect inhibition assays demonstrated a promising anti SARS-CoV2 for
bark EO, with a significant selectivity index of 17.5. The results suggested using this EO or its individual components for the protection against or treatment of COVID-19.
Quorum sensing (QS) controls the production of several bacterial virulence factors. There is accumulative evidence to support that targeting QS can ensure a significant diminishing of bacterial ...virulence. Lessening bacterial virulence has been approved as an efficient strategy to overcome the development of antimicrobial resistance. The current study aimed to assess the anti-QS and anti-virulence activities of α-adrenoreceptor prazosin against three virulent Gram-negative bacteria Pseudomonades aeruginosa, Proteus mirabilis, and Serratia marcescens. The evaluation of anti-QS was carried out on a series of in vitro experiments, while the anti-virulence activities of prazosin were tested in an in vivo animal model. The prazosin anti-QS activity was assessed on the production of QS-controlled Chromobacterium violaceum pigment violacein and the expression of QS-encoding genes in P. aeruginosa. In vitro tests were performed to evaluate the prazosin effects on biofilm formation and production of extracellular enzymes by P. aeruginosa, P. mirabilis, and S. marcescens. A protective assay was conducted to evaluate the in vivo anti-virulence activity of prazosin against P. aeruginosa, P. mirabilis, and S. marcescens. Moreover, precise in silico molecular docking was performed to test the prazosin affinity to different QS receptors. The results revealed that prazosin significantly decreased the production of violacein and the virulent enzymes, protease and hemolysins, in the tested strains. Prazosin significantly diminished biofilm formation in vitro and bacterial virulence in vivo. The prazosin anti-QS activity was proven by its downregulation of QS-encoding genes and its obvious binding affinity to QS receptors. In conclusion, prazosin could be considered an efficient anti-virulence agent to be used as an adjuvant to antibiotics, however, it requires further pharmacological evaluations prior to clinical application.
Currently, the treatment of Proteus mirabilis infections is considered to be complicated as the organism has become resistant to numerous antibiotic classes. Therefore, new inhibitors should be ...developed, targeting bacterial molecular functions. Methionine tRNA synthetase (MetRS), a member of the aminoacyl-tRNA synthetase family, is essential for protein biosynthesis offering a promising target for novel antibiotics discovery. In the context of computer-aided drug design (CADD), the current research presents the construction and analysis of a comparative homology model for P. mirabilis MetRS, enabling development of novel inhibitors with greater selectivity. Molecular Operating Environment (MOE) software was used to build a homology model for P. mirabilis MetRS using Escherichia coli MetRS as a template. The model was evaluated, and the active site of the target protein predicted from its sequence using conservation analysis. Molecular dynamic simulations were performed to evaluate the stability of the modeled protein structure. In order to evaluate the predicted active site interactions, methionine (the natural substrate of MetRS) and several inhibitors of bacterial MetRS were docked into the constructed model using MOE. After validation of the model, pharmacophore-based virtual screening for a systemically prepared dataset of compounds was performed to prove the feasibility of the proposed model, identifying possible parent compounds for further development of MetRS inhibitors against P. mirabilis.
We designed and synthesised novel quinazolinone tethered phenyl urea derivatives (
) that triple target the double mutant EGFR
, COX-2, and 15-LOX. Compounds (
,
,
,
, and
) not only had low ...micromolar IC50 inhibitory activities against the three targets, but they also showed good selectivity for COX-2 over COX-1 and for EGFR
over wild-type EGFR. Except for
and
, all of the tested compounds inhibited the NO production significantly more potently than celecoxib, diclofenac, and indomethacin. Compounds
and
reduced ROS levels more effectively than celecoxib and diclofenac. In terms of inhibiting TNF-α production,
treated cells showed TNF-α level, which is ∼10 times lower than celecoxib. Furthermore,
and
had the highest anticancer activity against the breast cancer cell line BT-459 with growth inhibition percentages of 67.14 and 70.07%, respectively. Docking studies confirm their favoured binding affinity. The proposed compounds could be promising multi-targeted leads.
The repurposing of drugs is one of the most competent strategies for discovering new antimicrobial agents. Vildagliptin is a dipeptidyl peptidase-4 inhibitor (DPI-4) that is used effectively in ...combination with metformin to control blood glucose levels in diabetic patients. This study was designed to evaluate the anti-virulence activities of this combination against one of the most clinically important pathogens,
. The current findings show a significant ability of the vildagliptin-metformin combination to diminish biofilm formation, bacterial motility, and the production of virulent extracellular enzymes and pyocyanin pigment. Furthermore, this drug combination significantly increased the susceptibility of
to oxidative stress, indicating immunity enhancement in the eradication of bacterial cells. In compliance with the in vitro findings, the histopathological photomicrographs of mice showed a considerable protective effect of the metformin-vildagliptin combination against
, revealing relief of inflammation due to
-induced pathogenesis.
mainly employs quorum sensing (QS) systems to control the production of its huge arsenal of virulence factors. The anti-virulence activities of the metformin-vildagliptin combination can be interrupted by the anti-QS activities of both metformin and vildagliptin, as both exhibited a considerable affinity to QS receptors. Additionally, the metformin-vildagliptin combination significantly downregulated the expression of the main three QS-encoding genes in
. These findings show the significant anti-virulence activities of metformin-vildagliptin at very low concentrations (10, 1.25 mg/mL, respectively) compared to the concentrations (850, 50 mg/mL, respectively) used to control diabetes.
Ulcerative colitis (UC) is an inflammatory bowel disease that is often resistant to current treatment options, leading to a need for alternative therapies. Herbal products have shown promise in ...managing various conditions, including UC. However, the potential of
branchlets ethanolic extract (CGBRE) in treating UC has not been explored. This study aimed to analyze the chemical composition of CGBRE and evaluate its efficacy in UC treatment through
and
experiments. LC-ESI-MS/MS was used to identify 86 compounds in CGBRE, with 21 potential bioactive compounds determined through pharmacokinetic analysis. Network pharmacology analysis revealed 171 potential UC targets for the bioactive compounds, including EGFR, LRRK2, and HSP90 as top targets, which were found to bind to key CGBRE compounds through molecular docking. Molecular docking findings suggested that CGBRE may be effective in the prevention or treatment of ulcerative colitis mediated by these proteins, where key CGBRE compounds exhibited good binding affinities through formation of numerous interactions.
studies in rats with acetic acid-induced UC demonstrated that oral administration of 300 mg/kg CGBRE for 6 days reduced UC symptoms and colonic expression of EGFR, LRRK2, and HSP90. These findings supported the therapeutic potential of CGBRE in UC and suggested the need for further preclinical and clinical investigation.
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