scholarly journals Assessing In Vitro Resistance Development in Enterovirus A71 in the Context of Combination Antiviral Treatment

2021 ◽  
Author(s):  
Kristina Lanko ◽  
Chenyan Shi ◽  
Shivaprasad Patil ◽  
Leen Delang ◽  
Jelle Matthijnssens ◽  
...  
Keyword(s):  
Antiviral Treatment ◽  
Resistance Development ◽  
Enterovirus A71

scholarly journals Assessing the in vitro resistance development in Enterovirus 71 in the context of combination antiviral treatment

2020 ◽  
Author(s):  
Kristina Lanko ◽  
Chenyan Shi ◽  
Shivaprasad Patil ◽  
Leen Delang ◽  
Jelle Matthijnssens ◽  
...  
Keyword(s):  
Antiviral Treatment ◽  
Enterovirus 71 ◽  
Sequencing Analysis ◽  
Resistance Development ◽  
Development Of Resistance ◽  
Enterovirus A71 ◽  
Polymerase Inhibitor ◽  
Direct Acting ◽  
Deep Sequencing Analysis

AbstractThere are currently no antivirals available to treat infection with enterovirus A71 (EV-A71) or any other enterovirus. The extensively studied capsid binders select rapidly for drug-resistant variants. We here explore whether the combination of two direct-acting enterovirus inhibitors with a different mechanism of action may delay or prevent resistance development to the capsid binders. To that end, the in vitro dynamics of resistance development to the capsid binder pirodavir was studied either alone or in combination with (i) a viral 2C-targeting compound (SMSK_0213), (ii) a viral 3C-protease inhibitor (rupintrivir) or (iii) a viral RNA-dependent RNA polymerase (RdRp) inhibitor [7-deaza-2’C-methyladenosine (7DMA)]. We demonstrate that combining pirodavir with either rupintrivir or the nucleoside analogue 7DMA delays the development of resistance to pirodavir and that no resistance to the protease or polymerase inhibitor develops. The combination of pirodavir with the 2C inhibitor results in a double-resistant virus population. The deep sequencing analysis of resistant populations revealed that even though resistant mutations are present in less than 30% of the population, this still provides the resistant phenotype.

Synthetic and semi-synthetic drugs as promising therapeutic option for the treatment of COVID-19

2020 ◽  
Vol 20 ◽  
Author(s):  
Ekta Shirbhate ◽  
Preeti Patel ◽  
Vijay K Patel ◽  
Ravichandran Veerasamy ◽  
Prabodh C Sharma ◽  
...  
Keyword(s):  
Therapeutic Option ◽  
Antiviral Treatment ◽  
The Novel ◽  
Clinical Experiences ◽  
Synthetic Compounds ◽  
Synthetic Drugs ◽  
Global Pandemic ◽  
The World ◽  
Novel Coronavirus

: The novel coronavirus disease-19 (COVID-19), a global pandemic that emerged from Wuhan, China has today travelled all around the world, so far 216 countries or territories with 21,732,472 people infected and 770,866 deaths globally (as per WHO COVID-19 update dated August 18, 2020). Continuous efforts are being made to repurpose the existing drugs and develop vaccines for combating this infection. Despite, to date, no certified antiviral treatment or vaccine prevails. Although, few candidates have displayed their efficacy in in vitro studies and are being repurposed for COVID-19 treatment. This article summarizes synthetic and semi-synthetic compounds displaying potent activity in their clinical experiences or studies against COVID-19 and also focuses on mode of action of drugs being repositioned against COVID-19.

scholarly journals Pseudomonas aeruginosa PAO 1 In Vitro Time–Kill Kinetics Using Single Phages and Phage Formulations—Modulating Death, Adaptation, and Resistance

Antibiotics ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 877
Author(s):  
Ana Mafalda Pinto ◽  
Alberta Faustino ◽  
Lorenzo M. Pastrana ◽  
Manuel Bañobre-López ◽  
Sanna Sillankorva
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Phage Therapy ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Chronic Infections ◽  
Swarming Motility ◽  
Resistance Development ◽  
Healthcare Settings ◽  
Time Kill

Pseudomonas aeruginosa is responsible for nosocomial and chronic infections in healthcare settings. The major challenge in treating P. aeruginosa-related diseases is its remarkable capacity for antibiotic resistance development. Bacteriophage (phage) therapy is regarded as a possible alternative that has, for years, attracted attention for fighting multidrug-resistant infections. In this work, we characterized five phages showing different lytic spectrums towards clinical isolates. Two of these phages were isolated from the Russian Microgen Sextaphage formulation and belong to the Phikmvviruses, while three Pbunaviruses were isolated from sewage. Different phage formulations for the treatment of P. aeruginosa PAO1 resulted in diversified time–kill outcomes. The best result was obtained with a formulation with all phages, prompting a lower frequency of resistant variants and considerable alterations in cell motility, resulting in a loss of 73.7% in swimming motility and a 79% change in swarming motility. These alterations diminished the virulence of the phage-resisting phenotypes but promoted their growth since most became insensitive to a single or even all phages. However, not all combinations drove to enhanced cell killings due to the competition and loss of receptors. This study highlights that more caution is needed when developing cocktail formulations to maximize phage therapy efficacy. Selecting phages for formulations should consider the emergence of phage-resistant bacteria and whether the formulations are intended for short-term or extended antibacterial application.

Antiviral activity of Mulberroside C against enterovirus A71 in vitro and in vivo

2021 ◽  
pp. 174204
Author(s):  
Yiming Cao ◽  
En Lei ◽  
Lei Li ◽  
Jin Ren ◽  
Xiaoyang He ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Enterovirus A71

Licochalcone A inhibits enterovirus A71 replication in vitro and in vivo

2021 ◽  
pp. 105091
Author(s):  
Yiming Cao ◽  
En Lei ◽  
Xiaolong Wang ◽  
Xiangyun Qi ◽  
Lei Li ◽  
...  
Keyword(s):  
Licochalcone A ◽  
Enterovirus A71

scholarly journals Development of Resistance in Wild-Type and Hypermutable Pseudomonas aeruginosa Strains Exposed to Clinical Pharmacokinetic Profiles of Meropenem and Ceftazidime Simulated In Vitro

2007 ◽  
Vol 51 (10) ◽  
pp. 3642-3649 ◽  
Author(s):  
Beate Henrichfreise ◽  
Irith Wiegand ◽  
Ingeborg Luhmer-Becker ◽  
Bernd Wiedemann
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Parent Strain ◽  
Resistance Mechanisms ◽  
In Vitro Models ◽  
Wild Type ◽  
Resistance Development ◽  
Development Of Resistance ◽  
Pharmacokinetic Profiles ◽  
Mutant Prevention Concentration

ABSTRACT In this study we investigated the interplay of antibiotic pharmacokinetic profiles and the development of mutation-mediated resistance in wild-type and hypermutable Pseudomonas aeruginosa strains. We used in vitro models simulating profiles of the commonly used therapeutic drugs meropenem and ceftazidime, two agents with high levels of antipseudomonal activity said to have different potentials for stimulating resistance development. During ceftazidime treatment of the wild-type strain (PAO1), fully resistant mutants overproducing AmpC were selected rapidly and they completely replaced wild-type cells in the population. During treatment with meropenem, mutants of PAO1 were not selected as rapidly and showed only intermediate resistance due to the loss of OprD. These mutants also replaced the parent strain in the population. During the treatment of the mutator P. aeruginosa strain with meropenem, the slowly selected mutants did not accumulate several resistance mechanisms but only lost OprD and did not completely replace the parent strain in the population. Our results indicate that the commonly used dosing regimens for meropenem and ceftazidime cannot avoid the selection of mutants of wild-type and hypermutable P. aeruginosa strains. For the treatment outcome, including the prevention of resistance development, it would be beneficial for the antibiotic concentration to remain above the mutant prevention concentration for a longer period of time than it does in present regimens.

scholarly journals In Vitro Time-Kill of Common Ocular Pathogens with Besifloxacin Alone and in Combination with Benzalkonium Chloride

2021 ◽  
Vol 14 (6) ◽  
pp. 517
Author(s):  
Joseph Blondeau ◽  
Heleen DeCory
Keyword(s):  
Staphylococcus Epidermidis ◽  
Benzalkonium Chloride ◽  
Bacterial Species ◽  
Drug Resistant ◽  
Resistance Development ◽  
Aureus Isolate ◽  
Killing Activity ◽  
Time Kill ◽  
Variable Impact

Background: Besifloxacin ophthalmic suspension 0.6% (w/v%) contains benzalkonium chloride (BAK) as a preservative. We evaluated the in vitro time-kill activity of besifloxacin, alone and in combination with BAK, against common bacteria implicated in ophthalmic infections. Methods: The activity of besifloxacin (100 µg/mL), BAK (10, 15, 20, and 100 µg/mL), and combinations of besifloxacin and BAK were evaluated against isolates of Staphylococcus epidermidis (n = 4), Staphylococcus aureus (n = 3), Haemophilus influenzae (n = 2), and Pseudomonas aeruginosa (n = 2) in time-kill experiments of 180 min duration. With the exception of one S. aureus isolate, all of the staphylococcal isolates were methicillin- and/or ciprofloxacin-resistant; one P. aeruginosa isolate was ciprofloxacin-resistant. The reductions in the viable colony counts (log10 CFU/mL) were plotted against time, and the differences among the time–kill curves were evaluated using an analysis of variance. Areas-under-the-killing-curve (AUKCs) were also computed. Results: Besifloxacin alone demonstrated ≥3-log killing of P. aeruginosa (<5 min) and H. influenzae (<120 min), and approached 3-log kills of S. aureus. BAK alone demonstrated concentration-dependent killing of S. epidermidis, S. aureus and H. influenzae, and at 100 µg/mL produced ≥3-log kills in <5 min against these species. The addition of BAK (10, 15, and 20 µg/mL) to besifloxacin increased the rate of killing compared to besifloxacin alone, with earlier 3-log kills of all species except P. aeruginosa and a variable impact on S. aureus. The greatest reductions in AUKC were observed among H. influenzae (8-fold) and S. epidermidis (≥5-fold). Similar results were found when the isolates were evaluated individually by their resistance phenotype. Conclusions: In addition to confirming the activity of 100 µg/mL BAK as a preservative in the bottle, these data suggest that BAK may help besifloxacin to achieve faster time-kills on-eye in the immediate timeframe post-instillation before extensive dilution against bacterial species implicated in ophthalmic infections, including drug-resistant S. epidermidis. Greater killing activity may help prevent resistance development and/or help treat resistant organisms.

Prevention and Detection of Fungicide Resistance Development in Rhizoctonia zeae from Soybean and Corn in Nebraska

2021 ◽  
Author(s):  
Nikita Gambhir ◽  
Srikanth Kodati ◽  
Matthew Huff ◽  
Flávio Silva ◽  
Olutoyosi Ajayi-Oyetunde ◽  
...  
Keyword(s):  
Fungicide Resistance ◽  
Resistance Management ◽  
Dry Weight ◽  
Geographic Region ◽  
Population Characteristics ◽  
Current Status ◽  
In Planta ◽  
Resistance Development ◽  
Rhizoctonia Zeae

The goal of this research was to advance the foundational knowledge required to quantify and mitigate fungicide resistance in Rhizoctonia zeae, the seedling disease pathogen of soybean and corn. In vitro sensitivity to azoxystrobin, fludioxonil, sedaxane, and/or prothioconazole was determined for 91 R. zeae isolates obtained mostly from soybean and corn fields in Nebraska. Isolates were sensitive to fludioxonil, sedaxane, and prothioconazole (EC50 < 3 µg/ml) and had a positively skewed EC50 distribution. Isolates were not sensitive to azoxystrobin in vitro (EC50 > 100 µg/ml) or in planta. Application of azoxystrobin did not significantly decrease disease severity or improve total dry weight of the soybean plants (P > 0.05). The risk of resistance development in R. zeae was estimated by characterizing its population structure. Eighty-one R. zeae isolates were genotyped using six microsatellite markers. Results showed that the population has a mixed mode of reproduction and is structured according to geographic region, suggesting limited dispersal. These population characteristics suggest that R. zeae has an intermediate risk of resistance development. Overall, this research established the current status of fungicide sensitivity in R. zeae in Nebraska and estimated its risk of resistance development, which can inform fungicide resistance management for R. zeae.

In silico screening of phytoconstituents with antiviral activities against SARS-COV-2 main protease, Nsp12 polymerase and Nsp13 helicase proteins

2021 ◽  
Vol 18 ◽  
Author(s):  
Jainey James ◽  
Divya Jyothi ◽  
Sneh Priya
Keyword(s):  
Antiviral Activity ◽  
Molecular Interactions ◽  
In Silico ◽  
Antiviral Treatment ◽  
In Vivo Studies ◽  
Main Protease ◽  
Hypothesis Model ◽  
Antiviral Activities ◽  
Pharmacophore Hypothesis

Aims: The present study aim was to analyse the molecular interactions of the phytoconstituents known for their antiviral activity with the SARS-CoV-2 nonstructural proteins such as main protease (6LU7), Nsp12 polymerase (6M71), and Nsp13 helicase (6JYT). The applied in silico methodologies was molecular docking and pharmacophore modeling using Schrodinger software. Methods: The phytoconstituents were taken from PubChem, and SARS-CoV-2 proteins were downloaded from the protein data bank. The molecular interactions, binding energy, ADMET properties and pharmacophoric features were analysed by glide XP, prime MM-GBSA, qikprop and phase application of Schrodinger respectively. The antiviral activity of the selected phytoconstituents was carried out by PASS predictor, online tools. Results: The docking score analysis showed that quercetin 3-rhamnoside (-8.77 kcal/mol) and quercetin 3-rhamnoside (-7.89 kcal/mol) as excellent products to bind with their respective targets such as 6LU7, 6M71 and 6JYT. The generated pharmacophore hypothesis model validated the docking results, confirming the hydrogen bonding interactions of the amino acids. The PASS online tool predicted constituent's antiviral potentials. Conclusion: The docked phytoconstituents showed excellent interactions with the SARS-CoV-2 proteins, and on the outset, quercetin 3-rhamnoside and quercetin 7-rhamnoside have well-interacted with all the three proteins, and these belong to the plant Houttuynia cordata. The pharmacophore hypothesis has revealed the characteristic features responsible for their interactions, and PASS prediction data has supported their antiviral activities. Thus, these natural compounds could be developed as lead molecules for antiviral treatment against SARS-CoV-2. Further in-vitro and in-vivo studies could be carried out to provide better drug therapy.

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