In vitro and in vivo activities of imipenem combined with BLI-489 against class D β-lactamase-producing Acinetobacter baumannii

2020 ◽  
Author(s):  
Yung-Chih Wang ◽  
Shu-Wei Huang ◽  
Ming-Hsien Chiang ◽  
I-Ming Lee ◽  
Shu-Chen Kuo ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
In Silico ◽  
Active Sites ◽  
Synergistic Effects ◽  
Docking Analysis ◽  
In Silico Docking ◽  
Class D ◽  
Time Kill

Abstract Background According to our preliminary study, BLI-489 has the potential to inhibit the hydrolysing activity of OXA-51-like β-lactamase produced by carbapenem-resistant Acinetobacter baumannii (CRAb). Objectives In the present study, the in vitro and in vivo activities of imipenem combined with BLI-489 against CRAb producing carbapenem-hydrolysing class D β-lactamases (CHDLs), namely OXA-23, OXA-24, OXA-51 and OXA-58, were determined. Methods A chequerboard analysis of imipenem and BLI-489 was performed using 57 and 7 clinical CRAb isolates producing different CHDLs and MBLs, respectively. Four representative strains harbouring different CHDL genes were subjected to a time–kill assay to evaluate the synergistic effects. An in silico docking analysis was conducted to simulate the interactions between BLI-489 and the different families of CHDLs. The in vivo activities of this combination were assessed using a Caenorhabditis elegans survival assay and a mouse pneumonia model. Results Chequerboard analysis showed that imipenem and BLI-489 had a synergistic effect on 14.3, 92.9, 100, 16.7 and 100% of MBL-, OXA-23-, OXA-24-like-, OXA-51-like- and OXA-58-producing CRAb isolates, respectively. In the time–kill assay, imipenem and BLI-489 showed synergy against OXA-24-like-, OXA-51-like- and OXA-58-, but not OXA-23-producing CRAb isolates after 24 h. The in silico docking analysis showed that BLI-489 could bind to the active sites of OXA-24 and OXA-58 to confer strong inhibition activity. The combination of imipenem and BLI-489 exhibited synergistic effects for the rescue of CRAb-infected C. elegans and mice. Conclusions Imipenem combined with BLI-489 has synergistic effects against CHDL-producing CRAb isolates.

scholarly journals Comparative Molecular Docking Analysis of Phytoconstituents against Alzheimer’s Disease Targets- An In-Silico Approach

2021 ◽  
Vol 12 (2) ◽  
pp. 1579-1589
Author(s):  
Geethanjali T ◽  
Logesh Kumar S ◽  
Keerthish Sujan B ◽  
Lakshmi Prabhaa M ◽  
Khousikan K ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Alzheimer Disease ◽  
Medicinal Plants ◽  
Panax Ginseng ◽  
In Silico ◽  
Docking Analysis ◽  
In Silico Docking

Alzheimer's disease (AD) is the most common form of dementia and one of the leading causes of death. The Aim and objective of the present study is to perform in-silico docking analysis of the major active constituents identified in three Indian medicinal plants namely Convolvulus pluricaulis, Coriandrum sativum and Panax ginseng for its effectiveness against the targets of Alzheimer Disease. In-silico docking analysis was performed by Molegro Virtual Docker (MVD-2010, 4.2.0) and Schrodinger Mestro (V 11.8). In addition, Drug likeness property, pharmacokinetics (ADME) and safety profile prediction studies were performed to identify the best drug candidates using Qikpro and Toxicity Estimation Software Tool (T.E.S.T). The target for Alzheimer Disease is Acetylcholinesterase and Butyrylcholinesterase. The X-ray crystal co-ordinates of AChE (PDB ID: 4bdt) and BChE (PDB ID: 6eqq) obtained from the Protein Data Bank. The phytoconstituents of three medicinal plants were retrieved from PubChem compound database in mol format. The standard drugs Donepezil, Rivastigmine, Galantamine, Memantine was obtained from the drug bank in .mol format for comparison. It was analysed from the parameters of docking that the phytoconstituents from Panax ginseng showed better anti-Alzheimer activity compared to that of the standard drugs. Based on the research findings, further studies can be performed in in-vitro & in-vivo animal models of Alzheimer’s disease to establish the efficacy of promising phytoconstituents.

scholarly journals Oleuropein modulates over-proliferation of keratinocytes in mice with imiquimodmediated psoriasis and inhibits differentiation of TH17 cells through the JAK3/STAT3 axis

2020 ◽  
Author(s):  
Quan Shi ◽  
Qi He ◽  
Weiming Chen ◽  
Jianwen Long ◽  
Bo Zhang
Keyword(s):  
T Cells ◽  
In Silico ◽  
Th17 Cells ◽  
Skin Lesions ◽  
Docking Studies ◽  
Inflammatory Disorder ◽  
T Helper 17 ◽  
In Silico Docking

IntroductionOleuropein (OLP) is polyphenol obtained from olive oil; it is proved in Chinese traditional medicine for its use in disorders including autoimmune and inflammatory disorders. Psoriasis (PSR) is an autoimmune and inflammatory disorder triggered by T-helper-17 (Th17) cells.Material and methodsWe developed an imiquimod (IMQ)-mediated PSR model in mice to study the anti-inflammatory role of OLP in psoriasis. The mice were given 50 mg/kg and 100 mg/kg dose of OLP. Histology was done to assess the inflammation of lesions. Western blot analysis was done for JAK3/STAT3 in isolated T cells, expression of RORgt was done by RT-PCR. The In silico molecular docking studies were done for interaction of OLP with target protein STAT3 and JAK3.ResultsTreatment of OLP attenuated proliferation in IMQ-mediated keratinocytes, improved infiltration of CD3+ cells in the skin lesions and in CD4+ and CD8+ T cells and also ameliorated the levels of cytokines. In in vitro studies in isolated T cells, OLP blocked the differentiation of Th17 cells and also the levels of IL-17 and the JAK3/STAT3 pathway. The in silico docking showed that OLP had potential binding affinity with JAK3 and STAT3 which was parallel to in vivo and in vitro findings.ConclusionsOLP ameliorates psoriasis skin lesions by blocking Th17-mediated inflammation. OLP may be an interesting molecule for treating autoimmunity in psoriasis.

scholarly journals In vitro toxicity and in silico docking analysis of two novel selective AH-receptor modulators

2018 ◽  
Vol 52 ◽  
pp. 178-188 ◽  
Author(s):  
Selma Mahiout ◽  
Sara Giani Tagliabue ◽  
Atefeh Nasri ◽  
Iyekhoetin Matthew Omoruyi ◽  
Lars Pettersson ◽  
...  
Keyword(s):  
In Silico ◽  
In Vitro Toxicity ◽  
Ah Receptor ◽  
Docking Analysis ◽  
In Silico Docking ◽  
Receptor Modulators

scholarly journals In Silico Analysis of Sea Urchin Pigments as Potential Therapeutic Agents Against SARS-CoV-2: Main Protease (Mpro) as a Target.

2020 ◽  
Author(s):  
Tamara Rubilar ◽  
Elena Susana Barbieri ◽  
Ayelén Gázquez ◽  
Marisa Avaro ◽  
Mercedes Vera-Piombo ◽  
...  
Keyword(s):  
Sea Urchin ◽  
In Silico ◽  
De Novo ◽  
Drug Repurposing ◽  
In Silico Analysis ◽  
Promising Alternative ◽  
In Silico Docking ◽  
Main Protease

The SARS-CoV-2 outbreak has spread rapidly and globally generating a new coronavirus disease (COVID-19) since December 2019 that turned into a pandemic. Effective drugs are urgently needed and drug repurposing strategies offer a promising alternative to dramatically shorten the process of traditional de novo development. Based on their antiviral uses, the potential affinity of sea urchin pigments to bind main protease (Mpro) of SARS-CoV-2 was evaluated in silico. Docking analysis was used to test the potential of these sea urchin pigments as therapeutic and antiviral agents. All pigment compounds presented high molecular affinity to Mpro protein. However, the 1,4-naphtoquinones polihydroxilate (Spinochrome A and Echinochrome A) showed high affinity to bind around the Mpro´s pocket target by interfering with proper folding of the protein mainly through an H-bond with Glu166 residue. This interaction represents a potential blockage of this protease´s activity. All these results provide novel information regarding the uses of sea urchin pigments as antiviral drugs and suggest the need for further in vitro and in vivo analysis to expand all therapeutic uses against SARS-CoV-2. <br>

scholarly journals In Vitro and In Vivo Activity of AS101 against Carbapenem-Resistant Acinetobacter baumannii

2021 ◽  
Vol 14 (8) ◽  
pp. 823
Author(s):  
Tsung-Ying Yang ◽  
Sung-Pin Tseng ◽  
Heather Nokulunga Dlamini ◽  
Po-Liang Lu ◽  
Lin Lin ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Antibacterial Activities ◽  
Treated Group ◽  
Infection Model ◽  
High Dose ◽  
Mouse Infection Model ◽  
Carbapenem Resistant ◽  
Time Kill

The increasing trend of carbapenem-resistant Acinetobacter baumannii (CRAB) worldwide has become a concern, limiting therapeutic alternatives and increasing morbidity and mortality rates. The immunomodulation agent ammonium trichloro (dioxoethylene-O,O′-) tellurate (AS101) was repurposed as an antimicrobial agent against CRAB. Between 2016 and 2018, 27 CRAB clinical isolates were collected in Taiwan. The in vitro antibacterial activities of AS101 were evaluated using broth microdilution, time-kill assay, reactive oxygen species (ROS) detection and electron microscopy. In vivo effectiveness was assessed using a sepsis mouse infection model. The MIC range of AS101 for 27 CRAB isolates was from 0.5 to 32 µg/mL, which is below its 50% cytotoxicity (approximately 150 µg/mL). Bactericidal activity was confirmed using a time-kill assay. The antibacterial mechanism of AS101 was the accumulation of the ROS and the disruption of the cell membrane, which, in turn, results in cell death. The carbapenemase-producing A. baumannii mouse sepsis model showed that AS101 was a better therapeutic effect than colistin. The mice survival rate after 120 h was 33% (4/12) in the colistin-treated group and 58% (7/12) in the high-dose AS101 (3.33 mg/kg/day) group. Furthermore, high-dose AS101 significantly decreased bacterial population in the liver, kidney and spleen (all p < 0.001). These findings support the concept that AS101 is an ideal candidate for further testing in future studies.

scholarly journals in Silico Docking and Molecular Dynamic Simulation of 3-Dehydroquinate Dehydratase from Mycobacterium Tuberculosis Through Virtual Screening and Pharmacokinetics Studies

2020 ◽  
Author(s):  
Mustafa Alhaji Isa ◽  
Muhammad M Ibrahim
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Virtual Screening ◽  
Molecular Dynamic ◽  
In Silico ◽  
Md Simulation ◽  
Binding Energies ◽  
In Silico Docking ◽  
Pharmacokinetic Properties

The 3-hydroquinate synthase (DHQase) is an enzyme that catalyzes the third step of the shikimate pathway in <i>Mycobacterium tuberculosis</i> (MTB), by converting 3-dehydroquinate into 3-dehydroshikimate. In this study, the novel inhibitors of DHQase from MTB was identified using in silico approach. The crystal structure of DHQase bound to 1,3,4-trihydroxy-5-(3-phenoxypropyl)-cyclohexane-1-carboxylic acid (CA) obtained from the Protein Data Bank (PDB ID: 3N76). The structure prepared through energy minimization and structure optimization. A total of 9699 compounds obtained from Zinc and PubChem databases capable of binding to DHQase and subjected to virtual screening through Lipinski’s rule of five and molecular docking analysis. Eight (8) compounds with good binding energies, ranged between ─8.99 to ─8.39kcal/mol were selected, better than the binding energy of ─4.93kcal/mol for CA and further filtered for pharmacokinetic properties (Absorption, Distribution, Metabolism, Excretion, and Toxicity or ADMET). Five compounds (ZINC14981770, ZINC14741224, ZINC14743698, ZINC13165465, and ZINC8442077) which had desirable pharmacokinetic properties selected for molecular dynamic (MD) simulation and molecular generalized born surface area (MM-GBSA) analyses. The results of the analyses showed that all the compounds formed stable and rigid complexes after the 50ns MD simulation and also had a lower binding as compared to CA. Therefore, these compounds considered as good inhibitors of MTB after in vitro and in vivo validation.”

scholarly journals In Silico Analysis of Sea Urchin Pigments as Potential Therapeutic Agents Against SARS-CoV-2: Main Protease (Mpro) as a Target.

2020 ◽  
Author(s):  
Tamara Rubilar ◽  
Elena Susana Barbieri ◽  
Ayelén Gázquez ◽  
Marisa Avaro ◽  
Mercedes Vera-Piombo ◽  
...  
Keyword(s):  
Sea Urchin ◽  
In Silico ◽  
De Novo ◽  
Drug Repurposing ◽  
In Silico Analysis ◽  
Promising Alternative ◽  
In Silico Docking ◽  
Main Protease

The SARS-CoV-2 outbreak has spread rapidly and globally generating a new coronavirus disease (COVID-19) since December 2019 that turned into a pandemic. Effective drugs are urgently needed and drug repurposing strategies offer a promising alternative to dramatically shorten the process of traditional de novo development. Based on their antiviral uses, the potential affinity of sea urchin pigments to bind main protease (Mpro) of SARS-CoV-2 was evaluated in silico. Docking analysis was used to test the potential of these sea urchin pigments as therapeutic and antiviral agents. All pigment compounds presented high molecular affinity to Mpro protein. However, the 1,4-naphtoquinones polihydroxilate (Spinochrome A and Echinochrome A) showed high affinity to bind around the Mpro´s pocket target by interfering with proper folding of the protein mainly through an H-bond with Glu166 residue. This interaction represents a potential blockage of this protease´s activity. All these results provide novel information regarding the uses of sea urchin pigments as antiviral drugs and suggest the need for further in vitro and in vivo analysis to expand all therapeutic uses against SARS-CoV-2. <br>

scholarly journals In Vitro Activities of Colistin and Sitafloxacin Combinations against Multidrug-, Carbapenem-, and Colistin-Resistant Acinetobacter baumannii Using the Broth Microdilution Checkerboard and Time-Kill Methods

Antibiotics ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 516
Author(s):  
Vipavee Rodjun ◽  
Jantana Houngsaitong ◽  
Preecha Montakantikul ◽  
Taniya Paiboonvong ◽  
Piyatip Khuntayaporn ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Clinical Studies ◽  
Tertiary Care ◽  
Resistant Isolate ◽  
Drug Resistant ◽  
Broth Microdilution ◽  
Time Kill ◽  
Tertiary Care Hospitals

Drug-resistant Acinetobacter baumannii (A. baumannii) infections are a critical global problem, with limited treatment choices. This study aims to determine the in vitro activities of colistin–sitafloxacin combinations against multidrug-, carbapenem- and colistin-resistant A. baumannii (MDR-AB, CRAB, CoR-AB, respectively) clinical isolates from tertiary care hospitals. We used the broth microdilution checkerboard and time-kill methods in this study. Synergy was found using both methods. The colistin–sitafloxacin combination showed synergy in MDR-AB, CRAB, and CoR-AB isolates (3.4%, 3.1%, and 20.9%, respectively). No antagonism was found in any type of drug-resistant isolate. The majority of CoR-AB isolates became susceptible to colistin (95.4%). The time-kill method also showed that this combination could suppress regrowth back to the initial inocula of all representative isolates. Our results demonstrated that the colistin–sitafloxacin combination might be an interesting option for the treatment of drug-resistant A. baumannii. However, further in vivo and clinical studies are required.

In vitro and in vivo synergistic effects of tigecycline combined with aminoglycosides on carbapenem-resistant Klebsiella pneumoniae

2021 ◽  
Author(s):  
Wentao Ni ◽  
Deqing Yang ◽  
Jie Guan ◽  
Wen Xi ◽  
Dexun Zhou ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Synergistic Effects ◽  
Molecular Characteristics ◽  
Synergistic Activity ◽  
Significant Activity ◽  
Clinical Pharmacokinetics ◽  
Carbapenem Resistant ◽  
Time Kill

Abstract Objectives Carbapenem-resistant Klebsiella pneumoniae (CR-KP) infections represent severe threats to public health worldwide. The aim of this study was to assess potential synergistic interaction between tigecycline and aminoglycosides via in vitro and in vivo studies. Methods Antibiotic resistance profiles and molecular characteristics of 168 CR-KP clinical isolates were investigated by susceptibility testing, PCR and MLST. Chequerboard tests and time–kill assays were performed for 20 CR-KP isolates to evaluate in vitro synergistic effects of tigecycline combined with aminoglycosides. A tissue-cage infection model of rats was established to evaluate in vivo synergistic effects. Different doses of tigecycline and aminoglycosides alone or in combination were administered for 7 days via tail vein injection. Antibiotic efficacy was evaluated in tissue-cage fluid and emergence of resistance was screened. Results The chequerboard tests showed that this combination displayed synergistic or partial synergistic activity against CR-KP. The time–kill assays further demonstrated that strong synergistic effects of such a combination existed against isolates that were susceptible to both drugs but for resistant isolates no synergy was observed if clinical pharmacokinetics were taken into consideration. The in vivo study showed that the therapeutic effectiveness of combination therapies was better than that of monotherapy for susceptible isolates, suggesting in vivo synergistic effects. Furthermore, combinations of tigecycline with an aminoglycoside showed significant activity in reducing the occurrence of tigecycline-resistant mutants. Conclusions Compared with single drugs, tigecycline combined with aminoglycosides could exert synergistic effects and reduce the emergence of tigecycline resistance. Such a combination might be an effective alternative when treating CR-KP infections in clinical practice.

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