scholarly journals Identification of Novel Anthracycline Resistance Genes and Their Inhibitors

2021 ◽  
Vol 14 (10) ◽  
pp. 1051
Author(s):  
Onat Kadioglu ◽  
Mohamed Elbadawi ◽  
Edmond Fleischer ◽  
Thomas Efferth
Keyword(s):  
Drug Resistance ◽  
Molecular Docking ◽  
Drug Repurposing ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Hek293 Cells ◽  
Transfected Cells ◽  
Anthracycline Resistance ◽  
Approved Drugs ◽  
Sensitizing Effect

Differentially expressed genes have been previously identified by us in multidrug-resistant tumor cells mainly resistant to doxorubicin. In the present study, we exemplarily focused on some of these genes to investigate their causative relationship with drug resistance. HMOX1, NEIL2, and PRKCA were overexpressed by lentiviral-plasmid-based transfection of HEK293 cells. An in silico drug repurposing approach was applied using virtual screening and molecular docking of FDA-approved drugs to identify inhibitors of these new drug-resistant genes. Overexpression of the selected genes conferred resistance to doxorubicin and daunorubicin but not to vincristine, docetaxel, and cisplatin, indicating the involvement of these genes in resistance to anthracyclines but not to a broader MDR phenotype. Using virtual drug screening and molecular docking analyses, we identified FDA-approved compounds (conivaptan, bexarotene, and desloratadine) that were interacting with HMOX1 and PRKCA at even stronger binding affinities than 1-(adamantan-1-yl)-2-(1H-imidazol-1-yl)ethenone and ellagic acid as known inhibitors of HMOX1 and PRKCA, respectively. Conivaptan treatment increased doxorubicin sensitivity of both HMOX1- and PRKCA-transfected cell lines. Bexarotene treatment had a comparable doxorubicin-sensitizing effect in HMOX1-transfected cells and desloratadine in PRKCA-transfected cells. Novel drug resistance mechanisms independent of ABC transporters have been identified that contribute to anthracycline resistance in MDR cells.

scholarly journals Comparative analytical evaluation of four centralized platforms for the detection of M. tuberculosis complex and resistance to rifampicin and isoniazid

2020 ◽  
Author(s):  
Margaretha de Vos ◽  
Lesley Scott ◽  
Anura David ◽  
Andre Trollip ◽  
Harald Hoffmann ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Limit Of Detection ◽  
Clinical Performance ◽  
Analytical Data ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Analytical Sensitivity ◽  
Isoniazid Resistance ◽  
Mdr Tb ◽  
Resistance Detection

Failure to rapidly identify drug-resistant tuberculosis (TB) increases the risk of patient mismanagement, the amplification of drug resistance and ongoing transmission. We generated comparative analytical data for four automated assays for detection of TB and multidrug-resistant (MDR) TB: Abbott RealTime MTB and MTB RIF/INH (Abbott), Hain Lifescience FluoroType® MTBDR (Hain), BD MAX™ MDR-TB (BD) and Roche cobas® MTB and MTB-RIF/INH (Roche). We included Xpert MTB/RIF (Xpert) and GenoType MTBDRplus as comparators for TB and drug resistance detection, respectively. We assessed analytical sensitivity for the detection of Mycobacterium tuberculosis complex using inactivated strains (M. tuberculosis H37Rv and M. bovis) spiked into TB-negative sputa and computed the 95% limit of detection (LOD95). We assessed the accuracy for rifampicin and isoniazid resistance detection using well characterized M. tuberculosis strains with high-confidence mutations accounting for >85% of first-line resistance mechanisms globally. For H37Rv and M. bovis, respectively, we measured LOD95 values of 3,781 and 2,926 (Xpert); 322 and 2,182 (Abbott); 826 and 4,301 (BD); 10,398 and 23,139 (Hain); 2,416 and 2,136 (Roche) genomes/mL. Assays targeting multi-copy genes or targets (Abbott, BD and Roche) showed increased analytical sensitivity compared to Xpert. Quantification of the panel by quantitative real-time PCR prevents the determination of absolute values and results reported here can only be interpreted for comparison purposes. All assays showed accuracy comparable to Genotype MTBDRplus for the detection of rifampicin and isoniazid resistance. The data from this analytical study suggest that the assays may have similar clinical performance to WHO-recommended molecular TB and MDR-TB assays.

scholarly journals The Action of Efflux Pump Genes in Conferring Drug Resistance to Klebsiella Species and Their Inhibition

2021 ◽  
Author(s):  
Priyanka Ashwath ◽  
Akhila Dharnappa Sannejal
Keyword(s):  
Drug Resistance ◽  
Antimicrobial Agents ◽  
Efflux Pump ◽  
Acquired Resistance ◽  
Efflux Pumps ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Klebsiella Species ◽  
Gram Negative ◽  
Multidrug Efflux Pumps

AbstractNosocomial infections caused by Klebsiella species are characterized by high rates of morbidity and mortality. The emergence of the multidrug-resistant (MDR) and extensive drug-resistant (XDR) Gram-negative bacteria reduces the antibiotic efficacy in the treatment of infections caused by the microorganisms. Management of these infections is often difficult, due to the high frequency of strains resistant to multiple antimicrobial agents. Multidrug efflux pumps play a major role as a mechanism of antimicrobial resistance in Gram-negative pathogens. Efflux systems are significant in conferring intrinsic and acquired resistance to the bacteria. The emergence of increasing drug resistance among Klebsiella pneumoniae nosocomial isolates has limited the therapeutic options for treatment of these infections and hence there is a constant quest for an alternative. In this review, we discuss various resistance mechanisms, focusing on efflux pumps and related genes in conferring resistance to Klebsiella. The role of various efflux pump inhibitors (EPIs) in restoring the antibacterial activity has also been discussed. In specific, antisense oligonucleotides as alternative therapeutics in combatting efflux-mediated resistance in Klebsiella species have focused upon.

scholarly journals Repurposing the Natural Compound for Antiviral During an Epidemic -a Case Study on the Drug Repurpose of Natural Compounds to Treat COVID-19

2020 ◽  
Author(s):  
Zhihao Wang ◽  
Chi Xu ◽  
Bing Liu ◽  
Nan Qiao
Keyword(s):  
Molecular Docking ◽  
In Silico ◽  
Natural Compound ◽  
Early Stage ◽  
Drug Repurposing ◽  
The United States ◽  
Natural Compounds ◽  
Global Scale ◽  
Novel Coronavirus ◽  
Approved Drugs

<p>The pandemic caused by the novel coronavirus SARS-CoV-2 is rapidly spreading and infecting the population on the global scale, it is a global health threat due to its high infection rate, high mortality and the lack of clinically approved drugs and vaccines for treating the disease (COVID-19). Utilising the published structures and homologue remodelling for proteins from SARS-CoV-2, an <i>in silico</i> molecular docking based screening was conducted and deposited in the Shennong project database. The results from the screening could be used to explain the clinical observation of repurposing the Ritonavir and Lopinavir to treat patients in the early stage of COVID-19 infection, and the prescription of Remdisivir in the United States as the therapy. Additionally, this molecular docking identified natural compound candidates for drug repurposing. This <i>in silico </i>molecular docking screen may be used for the initatial evaluation and rationalisation for drug repurposing of other potential candidates, especially other natural compounds from traditional Chinese medicines.</p>

scholarly journals Repurposing of RdRp Inhibitors against SARS-CoV-2 through Molecular Docking Tools

Coronaviruses ◽  
2020 ◽  
Vol 1 (1) ◽  
pp. 108-116 ◽  
Author(s):  
Rohit Bhatia ◽  
Raj Kumar Narang ◽  
Ravindra Kumar Rawal
Keyword(s):  
Amino Acids ◽  
Molecular Docking ◽  
Drug Repurposing ◽  
Mean Square ◽  
Mean Square Deviation ◽  
Rna Dependent Rna Polymerase ◽  
Hydrogen Bonding Interactions ◽  
Docking Protocol ◽  
Approved Drugs ◽  
2D And 3D

In the present hour, the COVID-19 pandemic needs no introduction. There is continuous and keen research in progress in order to discover or develop a suitable therapeutic candidate/vaccine against the fatal, severe acute respiratory syndrome causing coronavirus (SARS-CoV-2). Drug repurposing is an approach of utilizing the therapeutic potentials of previously approved drugs against some new targets or pharmacological responses. In the presented work, we have evaluated the RNA dependent RNA polymerase (RdRp) inhibitory potentials of FDA approved anti-viral drugs remdesivir, ribavirin, sofosbuvir and galidesivir through molecular docking. The studies were carried out using MOE 2019.0102 software against RdRp (PDB ID:7BTF, released on 8th April, 2020). All four drugs displayed good docking scores and significant binding interactions with the amino acids of the receptor. The docking protocol was validated by redocking of the ligands and the root mean square deviation (RMSD) value was found to be less than 2. The 2D and 3D binding patterns of the drugs were studied and evaluated with the help of poses. The drugs displayed excellent hydrogen bonding interactions within the cavity of the receptor and displayed comparable docking scores. These drugs may serve as new therapeutic candidates or leads against SARS-CoV-2.

In Silico Identification of Active Phytochemicals against COVID-19 by Targeting the SARS-CoV-2 Spike Glycoprotein Through Molecular Docking: A Drug Repurposing Approach

2021 ◽  
Vol 8 (2) ◽  
pp. 72-87
Author(s):  
Rathan Kumar
Keyword(s):  
Molecular Docking ◽  
Antiviral Treatment ◽  
Drug Repurposing ◽  
Modern Human ◽  
Binding Affinities ◽  
In Silico Identification ◽  
Adme Properties ◽  
Approved Drugs ◽  
Fda Approved Drugs ◽  
Natural Inhibitors

The spread of coronavirus disease (COVID-19) has become one of the most significant pandemics in modern human history, affecting more than 70 million people worldwide. Currently, only a few fda-approved drugs have suggested fighting the infection, in the absence of a specific antiviral treatment. Thus, repurposing the presently available drugs or using plant-based bioactive compounds can be the fastest possible solution. In this study, the computational methodology of molecular docking techniques was performed to screen and identify the viable potent inhibitors against the SARS-CoV-2 spike protein from a library of 200 active phytochemicals, based on their highest binding affinity towards the target protein. Later, the binding affinities of these phytochemicals were compared with that of the fda-approved drug fluvoxamine, which is currently in use against the mild COVID-19 patients. Out of these, 86 phytochemicals that exhibited better binding energy of value ≤-7.00kcal/mol, is selected for adme (absorption, distribution, metabolism, and excretion) analysis and drug likeliness studies to check the feasibility of these compounds. Wherein, 79 out of 86 phytochemicals showed a better theoretical affinity with sufficiently bearable adme properties. Thus, they can be the lead molecule for further investigation and validation processes towards developing natural inhibitors against the SARS-CoV-2 virus.

An in silico Approach to Identify Potential NDM-1 Inhibitors to Fight Multidrug Resistant Superbugs

2019 ◽  
Vol 14 (1) ◽  
pp. 79-84
Author(s):  
Seema Barman ◽  
Bonashree Phukan ◽  
Partha Sarathi Borah ◽  
Minakshi Puzari ◽  
Mohan Sharma ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Molecular Docking ◽  
Treatment Options ◽  
Quantitative Structure Activity Relationship ◽  
Multidrug Resistant ◽  
New Delhi ◽  
Gram Negative Bacteria ◽  
Global Threat ◽  
Relationship Assessment ◽  
Plant Sources

Background: Antibiotic resistance is a global threat and the emergence of Multi-Drug Resistant (MDR) bacteria compromises the treatment options, limiting the number of available drugs. New Delhi Metallo-beta-lactamase-1 (NDM-1) mediated drug resistance is one of the mechanisms associated with multidrug resistance. </P><P> Objective: In our study, reverse chemogenomics technique was applied for identification of potential NDM-1 inhibitors from plant sources to combat the issue of drug resistance in Gram-negative bacteria. </P><P> Method: Computational methodologies were employed to understand and validate the molecular interaction between the target protein and the ligands. A total of 22 plant-based compounds were screened for inhibitory activity against NDM-1 through subsequent comparative molecular docking. The compounds were passed through Lipinski filter and ADME-Tox filter, which represent an important part of drug discovery. </P><P> Result: On the basis of optimum molecular docking values, Garcinol was recognized as the most potential NDM-1 inhibitor. However, in Quantitative-Structure Activity Relationship assessment, Ajugasterone-C showed the least value of minimum inhibitory concentration. Most of the compounds were found to comply with Lipinski rule of 5 and showed good results in ADME-Tox filtration. </P><P> Conclusion: Garcinol and Ajugasterone-C were found to possess drug like characteristics and can act as potential NDM-1 inhibitors.

Lactobacillus rhamnosus cell-free extract targets virulence and antifungal drug resistance in Candida albicans

2020 ◽  
Vol 66 (12) ◽  
pp. 733-747
Author(s):  
Yvonne Dube ◽  
Amber Khan ◽  
Musa Marimani ◽  
Aijaz Ahmad
Keyword(s):  
Drug Resistance ◽  
Lactobacillus Rhamnosus ◽  
Chemical Characterization ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Gas Chromatography Mass Spectrometry ◽  
Drug Efflux ◽  
Antifungal Drug Resistance ◽  
Virulence Traits ◽  
Drug Efflux Pumps

Candidiasis caused by multidrug-resistant Candida species continues to be difficult to eradicate. The use of live probiotic bacteria has gained a lot of interest in the treatment of candidiasis; however, whole-cell probiotic use can often be associated with a high risk of sepsis. Strategies manipulating cell-free methods using probiotic strains could lead to the development of novel antifungal solutions. Therefore, we evaluated the effect of three probiotic cell-free extracts (CFEs) on the growth, virulence traits, and drug efflux pumps in C. albicans. On the basis of its minimum inhibitory concentration, Lactobacillus rhamnosus was selected and assessed against various virulence traits and drug resistance mechanisms. The results showed that L. rhamnosus CFE significantly inhibited hyphae formation and reduced secretion of proteinases and phospholipases. Moreover, L. rhamnosus inhibited the drug efflux proteins in resistant C. albicans strains thus reversing drug resistance. Gene expression data confirmed downregulation of genes associated with microbial virulence and drug resistance following treatment of C. albicans with L. rhamnosus CFE. Through gas chromatography – mass spectrometry chemical characterization, high contents of oleic acid (24.82%) and myristic acid (13.11%) were observed in this CFE. Collectively, our findings indicate that L. rhamnosus may potentially be used for therapeutic purposes to inhibit C. albicans infections.

scholarly journals Strategies to Combat Multidrug-Resistant and Persistent Infectious Diseases

Antibiotics ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 65 ◽  
Author(s):  
Olga Pacios ◽  
Lucia Blasco ◽  
Inès Bleriot ◽  
Laura Fernandez-Garcia ◽  
Mónica González Bardanca ◽  
...  
Keyword(s):  
Phage Therapy ◽  
Drug Repurposing ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Recurrent Infections ◽  
International Crisis ◽  
New Antibiotics ◽  
Persistent Bacteria ◽  
Antibiotic Failure ◽  
Almost All

Antibiotic failure is one of the most worrying health problems worldwide. We are currently facing an international crisis with several problematic facets: new antibiotics are no longer being discovered, resistance mechanisms are occurring in almost all clinical isolates of bacteria, and recurrent infections caused by persistent bacteria are hampering the successful treatment of infections. In this context, new anti-infectious strategies against multidrug-resistant (MDR) and persistent bacteria, as well as the rescue of Food and Drug Administration (FDA)-approved compounds (drug repurposing), are being explored. Among the highlighted new anti-infectious strategies, in this review, we focus on antimicrobial peptides, anti-virulence compounds, phage therapy, and new molecules. As drugs that are being repurposed, we highlight anti-inflammatory compounds, anti-psychotics, anti-helminthics, anti-cancerous drugs, and statins.

scholarly journals Combined Deep Learning and Molecular Docking Simulations Approach Identifies Potentially Effective FDA Approved Drugs for Repurposing Against SARS-CoV-2

2020 ◽  
Author(s):  
Muhammad Umer Anwar ◽  
Farjad Adnan ◽  
Asma Abro ◽  
Muhammad Rayyan Khan ◽  
Asad Ur Rehman ◽  
...  
Keyword(s):  
Deep Learning ◽  
Molecular Docking ◽  
Active Sites ◽  
Drug Repurposing ◽  
Viral Proteins ◽  
Penicillin G ◽  
Computational Approaches ◽  
Docking Simulations ◽  
Approved Drugs ◽  
Fda Approved Drugs

<p></p><p>The ongoing pandemic of Coronavirus Disease 2019 (COVID-19), the disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has posed a serious threat to global public health. Currently no approved drug or vaccine exists against SARS-CoV-2. Drug repurposing, represented as an effective drug discovery strategy from existing drugs, is a time efficient approach to find effective drugs against SARS-CoV-2 in this emergency situation. Both experimental and computational approaches are being employed in drug repurposing with computational approaches becoming increasingly popular and efficient. In this study, we present a robust experimental design combining deep learning with molecular docking experiments to identify most promising candidates from the list of FDA approved drugs that can be repurposed to treat COVID-19. We have employed a deep learning based Drug Target Interaction (DTI) model, called DeepDTA, with few improvements to predict drug-protein binding affinities, represented as KIBA scores, for 2,440 FDA approved and 8,168 investigational drugs against 24 SARS-CoV-2 viral proteins. FDA approved drugs with the highest KIBA scores were selected for molecular docking simulations. We ran docking simulations for 168 selected drugs against 285 total predicted and/or experimentally proven active sites of all 24 SARS-CoV-2 viral proteins. We used a recently published open source AutoDock based high throughput screening platform virtualflow to reduce the time required to run around 50,000 docking simulations. A list of 49 most promising FDA approved drugs with best consensus KIBA scores and AutoDock vina binding affinity values against selected SARS-CoV-2 viral proteins is generated. Most importantly, anidulafungin, velpatasvir, glecaprevir, rifabutin, procaine penicillin G, tadalafil, riboflavin 5’-monophosphate, flavin adenine dinucleotide, terlipressin, desmopressin, elbasvir, oxatomide, enasidenib, edoxaban and selinexor demonstrate highest predicted inhibitory potential against key SARS-CoV-2 viral proteins.</p><p></p>

Sign in / Sign up

Export Citation Format

Share Document