scholarly journals Small-molecule ligands can inhibit −1 programmed ribosomal frameshifting in a broad spectrum of coronaviruses

2021 ◽  
Author(s):  
Sneha Munshi ◽  
Krishna Neupane ◽  
Sandaru M Ileperuma ◽  
Matthew TJ Halma ◽  
Jamie A Kelly ◽  
...  
Keyword(s):  
Small Molecule ◽  
Broad Spectrum ◽  
Viral Proteins ◽  
Serine Protease Inhibitor ◽  
Viral Mrna ◽  
Ribosomal Frameshifting ◽  
Small Molecule Ligands ◽  
Spectrum Activity ◽  
Negative Controls ◽  
Broad Spectrum Activity

Recurrent outbreaks of novel zoonotic coronavirus (CoV) diseases since 2000 have high-lighted the importance of developing therapeutics with broad-spectrum activity against CoVs. Because all CoVs use −1 programmed ribosomal frameshifting (−1 PRF) to control expression of key viral proteins, the frameshift signal in viral mRNA that stimulates −1 PRF provides a promising potential target for such therapeutics. To test the viability of this strategy, we explored a group of 6 small-molecule ligands, evaluating their activity against the frameshift signals from a panel of representative bat CoVs—the most likely source of future zoonoses—as well as SARS-CoV-2 and MERS-CoV. We found that whereas some ligands had notable activity against only a few of the frameshift signals, the serine protease inhibitor nafamostat suppressed −1 PRF significantly in several of them, while having limited to no effect on −1 PRF caused by frameshift signals from other viruses used as negative controls. These results suggest it is possible to find small-molecule ligands that inhibit −1 PRF specifically in a broad spectrum of CoVs, establishing the frameshift signal as a viable target for developing pan-coronaviral therapeutics.

scholarly journals Anti-frameshifting ligand active against SARS coronavirus-2 is resistant to natural mutations of the frameshift-stimulatory pseudoknot

2020 ◽  
Author(s):  
Krishna Neupane ◽  
Sneha Munshi ◽  
Meng Zhao ◽  
Dustin B. Ritchie ◽  
Sandaru M. Ileperuma ◽  
...  
Keyword(s):  
Small Molecule ◽  
Viral Proteins ◽  
Therapeutic Strategies ◽  
Base Pairing ◽  
Sars Coronavirus ◽  
Ribosomal Frameshifting ◽  
Expression Levels ◽  
Viral Propagation ◽  
Small Molecule Ligands ◽  
Rna Pseudoknot

The coronavirus SARS-CoV-2 causing the COVID-19 pandemic uses −1 programmed ribosomal frameshifting (−1 PRF) to control the expression levels of key viral proteins. Because modulating −1 PRF can attenuate viral propagation, ligands binding to the viral RNA pseudoknot that stimulates −1 PRF may prove useful as therapeutics. Mutations in the pseudoknot have been observed over the course of the pandemic, but how they affect −1 PRF and the activity of inhibitors is unknown. Cataloguing natural mutations in all parts of the SARS-CoV-2 pseudoknot, we studied a panel of 6 mutations in key structural regions. Most mutations left the −1 PRF efficiency unchanged, even when base-pairing was disrupted, but one led to a remarkable three-fold decrease, suggesting that SARS-CoV-2 propagation may be less sensitive to modulation of −1 PRF efficiency than some other viruses. Examining the effects of one of the few small-molecule ligands known to suppress −1 PRF significantly in SARS-CoV, we found that it did so by similar amounts in all SARS-CoV-2 mutants tested, regardless of the basal −1 PRF efficiency, indicating that the activity of anti-frameshifting ligands can be resistant to natural pseudoknot mutations. These results have important implications for therapeutic strategies targeting SARS-CoV-2 through modulation of −1 PRF.

scholarly journals Five-Year Longitudinal Assessment (2008 to 2012) of E-101 Solution Activity against Clinical Target and Antimicrobial-Resistant Pathogens

2014 ◽  
Vol 58 (8) ◽  
pp. 4911-4914 ◽  
Author(s):  
Gerald A. Denys ◽  
Chris M. Pillar ◽  
Daniel F. Sahm ◽  
Peter O'Hanley ◽  
Jackson T. Stephens
Keyword(s):  
Broad Spectrum ◽  
Susceptibility Testing ◽  
Bacterial Species ◽  
Clinical Isolates ◽  
Longitudinal Assessment ◽  
Gram Negative ◽  
Spectrum Activity ◽  
Eskape Pathogens ◽  
Negative Target ◽  
Broad Spectrum Activity

ABSTRACTThis study summarizes the topical E-101 solution susceptibility testing results for 760 Gram-positive and Gram-negative target pathogens collected from 75 U.S. sites between 2008 and 2012 and 103 ESKAPE pathogens. E-101 solution maintained potent activity against all bacterial species studied for each year tested, with MICs ranging from <0.008 to 0.25 μg porcine myeloperoxidase (pMPO)/ml. These results confirm that E-101 solution retains its potent broad-spectrum activity against U.S. clinical isolates and organisms with challenging resistance phenotypes.

Efficacy of some medicated soaps and hand washes available in market

2021 ◽  
Vol 3 (1) ◽  
pp. 047-055
Author(s):  
Pimpliskar Mukesh ◽  
SoumyaGounder ◽  
Rahul Jadhav
Keyword(s):  
Broad Spectrum ◽  
Life Forms ◽  
Small Scale ◽  
Gram Positive ◽  
Consistent Finding ◽  
Gram Negative ◽  
Cross Transmission ◽  
Spectrum Activity ◽  
Significant Measure ◽  
Broad Spectrum Activity

Background: Handwashing is underlined as the absolute most significant measure to forestall cross-transmission of small-scale life forms and consequently to forestall nosocomial contaminations. Be that as it may, under routine emergency clinic practice consistent with this measure is still unsatisfactorily low, under half in many investigations distributed in the previous 20 years. This consistent finding is stressing because ongoing investigations have demonstrated that this degree of consistency won't decrease the danger of transmission of multi- medicate safe microscopic organisms in the emergency clinics. Results: In the present investigation effect of marketed hand washed namely Lifebuoy, Dettol and Savlon were tested on bacteria E. coli, S.aureus, S.pyogen, Klebshiella and, fungi Candida albicans. All the handwash at concentrated level found to be effective but only Dettol hand wash could give inhibitory action at 25ug/ml against Klebshiella while others at50ug/ml. Conclusions: Soapex and Dettol soap had broad spectrum activity as it inhibited the growth of Gram positive (Streptococcus pyogen) and Gram-negative (Escherichia coli). Liquid handwash such as Lifebuoy,Dettol and Savlon showed broad spectrum activity on both Gram-positive and Gram negative test microorganisms.

scholarly journals Correction: Novel broad-spectrum activity-based probes to profile malarial cysteine proteases

PLoS ONE ◽  
2020 ◽  
Vol 15 (3) ◽  
pp. e0231231
Author(s):  
Michele S. Y. Tan ◽  
Dara Davison ◽  
Mateo I. Sanchez ◽  
Bethany M. Anderson ◽  
Stephen Howell ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Cysteine Proteases ◽  
Spectrum Activity ◽  
Broad Spectrum Activity

scholarly journals Rational design, synthesis and testing of novel tricyclic topoisomerase inhibitors for the treatment of bacterial infections part 2

2020 ◽  
Vol 11 (12) ◽  
pp. 1379-1385
Author(s):  
R. Kirk ◽  
A. Ratcliffe ◽  
G. Noonan ◽  
M. Uosis-Martin ◽  
D. Lyth ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Bacterial Infections ◽  
Rational Design ◽  
Topoisomerase Ii ◽  
Topoisomerase Inhibitors ◽  
Design Synthesis ◽  
Pharmacokinetic Properties ◽  
Spectrum Activity ◽  
Broad Spectrum Activity

We disclose the discovery of REDX07965, a novel tricyclic topoisomerase inhibitor (NTTI) which has broad spectrum activity, favourable in vitro pharmacokinetic properties and selectivity versus human topoisomerase II.

Alkoxyphenylthiazoles with broad-spectrum activity against multidrug-resistant gram-positive bacterial pathogens

2018 ◽  
Vol 152 ◽  
pp. 318-328 ◽  
Author(s):  
Moustafa ElAwamy ◽  
Haroon Mohammad ◽  
Abdelrahman Hussien ◽  
Nader S. Abutaleb ◽  
Mohamed Hagras ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Bacterial Pathogens ◽  
Multidrug Resistant ◽  
Gram Positive ◽  
Spectrum Activity ◽  
Broad Spectrum Activity

scholarly journals Identification of Broad-Spectrum Antiviral Compounds by Targeting Viral Entry

Viruses ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 176 ◽  
Author(s):  
Michela Mazzon ◽  
Ana Ortega-Prieto ◽  
Douglas Imrie ◽  
Christin Luft ◽  
Lena Hess ◽  
...  
Keyword(s):  
Viral Entry ◽  
Broad Spectrum ◽  
Well Being ◽  
Screening Strategy ◽  
Life Cycles ◽  
Antiviral Compounds ◽  
Spectrum Activity ◽  
Cellular Pathways ◽  
Broad Spectrum Activity ◽  
Economic Well Being

Viruses are a major threat to human health and economic well-being. In recent years Ebola, Zika, influenza, and chikungunya virus epidemics have raised awareness that infections can spread rapidly before vaccines or specific antagonists can be made available. Broad-spectrum antivirals are drugs with the potential to inhibit infection by viruses from different groups or families, which may be deployed during outbreaks when specific diagnostics, vaccines or directly acting antivirals are not available. While pathogen-directed approaches are generally effective against a few closely related viruses, targeting cellular pathways used by multiple viral agents can have broad-spectrum efficacy. Virus entry, particularly clathrin-mediated endocytosis, constitutes an attractive target as it is used by many viruses. Using a phenotypic screening strategy where the inhibitory activity of small molecules was sequentially tested against different viruses, we identified 12 compounds with broad-spectrum activity, and found a subset blocking viral internalisation and/or fusion. Importantly, we show that compounds identified with this approach can reduce viral replication in a mouse model of Zika infection. This work provides proof of concept that it is possible to identify broad-spectrum inhibitors by iterative phenotypic screenings, and that inhibition of host-pathways critical for viral life cycles can be an effective antiviral strategy.

scholarly journals Manogepix (APX001A) Displays Potent In Vitro Activity against Human Pathogenic Yeast, but with an Unexpected Correlation to Fluconazole MICs

2020 ◽  
Vol 64 (7) ◽  
Author(s):  
Maiken Cavling Arendrup ◽  
Karin Meinike Jørgensen
Keyword(s):  
Amphotericin B ◽  
Broad Spectrum ◽  
Hot Spot ◽  
Its Sequencing ◽  
Wild Type ◽  
Pathogenic Yeast ◽  
Fluconazole Resistance ◽  
Content Type ◽  
Spectrum Activity ◽  
Broad Spectrum Activity

ABSTRACT Manogepix (APX001A) is the active moiety of the novel drug candidate fosmanogepix (APX001). We previously reported the broad-spectrum activity of manogepix but also observed a correlation between increased manogepix and fluconazole MICs. Here, we extended this study and included isolates with acquired fluconazole resistance. Isolates (n = 835) were identified using CHROMagar, matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS), and, when needed, internal transcribed spacer (ITS) sequencing. EUCAST E.Def 7.3.1 susceptibility testing included manogepix, amphotericin B, anidulafungin, micafungin, fluconazole, and voriconazole. Manogepix wild-type-upper-limit (WT-UL) values were established following EUCAST principles for the epidemiological cutoff value (ECOFF) setting allowing wild-type/non-wild-type classification. Drug-specific MIC correlations were investigated using Pearson’s correlation. Manogepix modal MICs were low (range, 0.004 to 0.06 mg/liter against 16/20 included species). Exceptions were Candida krusei and Candida inconspicua and, to a lesser extent, Candida kefyr and Pichia kluyveri. The activity was independent of Fks echinocandin hot spot alterations (n = 17). Adopting the WT-UL established for Candida albicans, Candida dubliniensis, Candida glabrata, Candida parapsilosis, and Candida tropicalis, 14/724 (1.9%) isolates were non-wild type for manogepix. Twelve of these (85.7%) were also non-wild type for fluconazole. A statistically significant correlation was observed between manogepix and fluconazole MICs for C. albicans, C. dubliniensis, C. glabrata, C. parapsilosis, and C. tropicalis (Pearson’s r = 0.401 to 0.575) but not between manogepix and micafungin or amphotericin B MICs for any species except C. tropicalis (r = 0.519 for manogepix versus micafungin). Broad-spectrum activity was confirmed for manogepix against contemporary yeast. However, a 1 to 4 2-fold dilutions increase in manogepix MICs is observed in a subset of isolates with acquired fluconazole resistance. Further studies on the potential underlying mechanism and implication for optimal dosing are warranted.

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