Elucidating the anti-biofilm and anti-quorum sensing potential of selenocystine against respiratory tract infections causing bacteria: in vitro and in silico studies

Abstract Bacteria are increasingly relying on biofilms to develop resistance to antibiotics thereby resulting in their failure in treating many infections. In spite of continuous research on many synthetic and natural compounds, ideal anti-biofilm molecule is still not found thereby warranting search for new class of molecules. The current study focuses on exploring anti-biofilm potential of selenocystine against respiratory tract infection (RTI)-causing bacteria. Anti-bacterial and anti-biofilm assays demonstrated that selenocystine inhibits the growth of bacteria in their planktonic state, and formation of biofilms while eradicating preformed-biofilm effectively. Selenocystine at a MIC50 as low as 42 and 28 μg/mL effectively inhibited the growth of Klebsiella pneumonia and Pseudomonas aeruginosa. The antibacterial effect is further reconfirmed by agar cup diffusion assay and growth-kill assay. Selenocystine showed 30–60% inhibition of biofilm formation in K. pneumonia, and 44–70% in P. aeruginosa respectively. It also distorted the preformed-biofilms by degrading the eDNA component of the Extracellular Polymeric Substance matrix. Molecular docking studies of selenocystine with quorum sensing specific proteins clearly showed that through the carboxylic acid moiety it interacts and inhibits the protein function, thereby confirming its anti-biofilm potential. With further validation selenocystine can be explored as a potential candidate for the treatment of RTIs.

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In-silico Studies of Isolated Phytoalkaloid Against Lipoxygenase: Study Based on Possible Correlation

Combinatorial Chemistry & High Throughput Screening ◽

10.2174/1386207321666180220125406 ◽

2018 ◽

Vol 21 (3) ◽

pp. 215-221

Author(s):

Haroon Khan ◽

Muhammad Zafar ◽

Helena Den-Haan ◽

Horacio Perez-Sanchez ◽

Mohammad Amjad Kamal

Keyword(s):

In Silico ◽

Docking Studies ◽

In Vivo Studies ◽

In Vitro Assays ◽

Chronic Obstructive ◽

Lipoxygenase Inhibitors ◽

Lipoxygenase Inhibition ◽

In Silico Studies

Aim and Objective: Lipoxygenase (LOX) enzymes play an important role in the pathophysiology of several inflammatory and allergic diseases including bronchial asthma, allergic rhinitis, atopic dermatitis, allergic conjunctivitis, rheumatoid arthritis and chronic obstructive pulmonary disease. Inhibitors of the LOX are believed to be an ideal approach in the treatment of diseases caused by its over-expression. In this regard, several synthetic and natural agents are under investigation worldwide. Alkaloids are the most thoroughly investigated class of natural compounds with outstanding past in clinically useful drugs. In this article, we have discussed various alkaloids of plant origin that have already shown lipoxygenase inhibition in-vitro with possible correlation in in silico studies. Materials and Methods: Molecular docking studies were performed using MOE (Molecular Operating Environment) software. Among the ten reported LOX alkaloids inhibitors, derived from plant, compounds 4, 2, 3 and 1 showed excellent docking scores and receptor sensitivity. Result and Conclusion: These compounds already exhibited in vitro lipoxygenase inhibition and the MOE results strongly correlated with the experimental results. On the basis of these in vitro assays and computer aided results, we suggest that these compounds need further detail in vivo studies and clinical trial for the discovery of new more effective and safe lipoxygenase inhibitors. In conclusion, these results might be useful in the design of new and potential lipoxygenase (LOX) inhibitors.

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Preliminary Report of In vitro and In vivo Effectiveness of Dornase Alfa on SARS-CoV-2 Infection (Preprint)

10.2196/preprints.20200 ◽

2020 ◽

Author(s):

Hacer Kuzu Okur ◽

Koray Yalcin ◽

Cihan Tastan ◽

Sevda Demir ◽

Bulut Yurtsever ◽

...

Keyword(s):

Cystic Fibrosis ◽

Respiratory Tract ◽

Mononuclear Cells ◽

Multiple Organ ◽

Peripheral Blood Mononuclear ◽

Dornase Alfa ◽

Tract Infections ◽

Adult Peripheral Blood

UNSTRUCTURED Dornase alfa, the recombinant form of the human DNase I enzyme, breaks down neutrophil extracellular traps (NET) that include a vast amount of DNA fragments, histones, microbicidal proteins and oxidant enzymes released from necrotic neutrophils in the highly viscous mucus of cystic fibrosis patients. Dornase alfa has been used for decades in patients with cystic fibrosis to reduce the viscoelasticity of respiratory tract secretions, to decrease the severity of respiratory tract infections, and to improve lung function. Previous studies have linked abnormal NET formations to lung diseases, especially to acute respiratory distress syndrome (ARDS). Coronavirus disease 2019 (COVID-19) pandemic affected more than two million people over the world, resulting in unprecedented health, social and economic crises. The COVID-19, viral pneumonia that progresses to ARDS and even multiple organ failure, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). High blood neutrophil levels are an early indicator of SARS-CoV-2 infection and predict severe respiratory diseases. A similar mucus structure is detected in COVID-19 patients due to the accumulation of excessive NET in the lungs. Here, we show our preliminary results with dornase alfa that may have an in-vitro anti-viral effect against SARS-CoV-2 infection in a bovine kidney cell line, MDBK without drug toxicity on healthy adult peripheral blood mononuclear cells. In this preliminary study, we also showed that dornase alfa can promote clearance of NET formation in both an in-vitro and three COVID-19 cases who showed clinical improvement in radiological analysis (2-of-3 cases), oxygen saturation (SpO2), respiratory rate, disappearing of dyspnea and coughing.

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A Prospective Open-Label Multicentre Trial on the Use of 1 G, Once Daily Ceftriaxone in Lower Respiratory Tract Infections

Canadian Journal of Infectious Diseases ◽

10.1155/1994/421905 ◽

1994 ◽

Vol 5 (suppl c) ◽

pp. 3C-8C ◽

Cited By ~ 1

Author(s):

Donald E Low ◽

Lionel A Mandell

Keyword(s):

Respiratory Tract ◽

Treatment Failure ◽

Lower Respiratory Tract ◽

Study Drug ◽

Open Label ◽

In Vitro Susceptibility ◽

Once Daily ◽

Minimal Inhibitory Concentrations ◽

Tract Infections

This prospective. single open-label sludy was conducted in 14 Canadian centres to assess lhe efncacy of I g, once a day intravenous ceftriaxone treatment administered for a minimum of three days in patients with lower respiratory tract infection. There were 137 patients enrolled. Age varied between 19 and 95 years (mean 68 years). Mosl patients (91 %) were diagnosed with community acquired pneumonia without bacteremia. Most of the cases (82%) were defined as modcralc or severe. Patients received ceftriaxone treatment for an average or five days. Macrolidcs or metronidazole were administered concomitantly wilh ceftriaxone in 34 patienls (25%). After a minimum of three days of ceftriaxone treatment. 59 palicnls (43%) were switched to oral antibiotics. Favourable treatment outcome was found in 92.9% and treatment failure (including relapse of infection) in 7.1 % o lpalicnls. Evaluable patients accounted for 91 % of patients enrolled in the study. Clinical cure and clinical improvement were achieved in 64.6 and 28.3% of the evaluable patients. respectively. Relapse of infection occurred in two patients (1.8%). and treatment failure was recorded in six cases (5.3%). Twelve patients (8.8%) died clue to reasons unrelated to the sludy treatment. Three adverse event (hives, diarrhea and phlebitis at the injection site) were possibly related to the study drug. A cross-Canada in vitro susceptibility surveillance study of bacterial pathogens. frequently the cause of pneumonia. found ceftriaxone to have minimal inhibitory concentrations in 90% of isolates that would support such a dosing regimen. with the exception of Enterobacter species. These rcsults support the use of 1 g, once daily ceftriaxone for the empirical treatment of pneumonia in those patients requiring hospitalization.

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Telithromycin: The First of the Ketolides

Annals of Pharmacotherapy ◽

10.1345/aph.1a038 ◽

2002 ◽

Vol 36 (3) ◽

pp. 452-464 ◽

Cited By ~ 37

Author(s):

Christopher S Shain ◽

Guy W Amsden

Keyword(s):

Respiratory Tract ◽

Clinical Efficacy ◽

Respiratory Tract Infections ◽

Safety Issue ◽

Qtc Interval ◽

Phagocytic Cells ◽

Medline Search ◽

Atypical Pathogens ◽

Tract Infections

OBJECTIVE: To review the chemistry, spectrum of activity, pharmacology, clinical efficacy, and safety of telithromycin. DATA SOURCES: A MEDLINE search from 1966 to December 2000 was performed via OVID and PubMed using the following search terms: HMR 3647, HMR3647, Ketek, RU 66647, and telithromycin. An extensive review of retrieved literature, abstracts from international scientific conferences, and minutes from regulatory authority meetings was also performed. DATA EXTRACTION: Medicinal chemistry, in vitro, animal, and human trials were reviewed for information on the antimicrobial activity, clinical efficacy, pharmacology, and safety of telithromycin. DATA SYNTHESIS: Several chemical modifications to the macrolide structure have led to the development of telithromycin, the first ketolide antimicrobial that demonstrates improved activity against penicillin- and macrolide/azalide-resistant Streptococcus pneumoniae due to its unique binding to the ribosomal target site. Although telithromycin may be useful in the treatment of community-acquired respiratory tract infections due to its activity against common typical and atypical pathogens, questions concerning its reliable activity against Haemophilus influenzae need to be addressed. Telithromycin's pharmacokinetics permit once-daily dosing for abbreviated periods and good distribution into lung tissue and phagocytic cells. Clinical and bacteriologic cure rates have been similar to those of comparator agents in human efficacy trials; however, the incidence of adverse gastrointestinal events were generally higher with telithromycin patients. Like other macrolides and many newer fluoroquinolones, telithromycin's ability to prolong the QTc interval is a potential safety issue, especially in elderly patients with predisposing conditions or those who are concurrently receiving drugs that are substrates for CYP2D6 and 3A4. Liver function test elevations demonstrated during clinical trials, although not overtly severe, may warrant monitoring in some patients taking multiple hepatically metabolized/cleared agents. CONCLUSIONS: Telithromycin offers potential advantages over traditional macrolides/azalides for community-acquired respiratory tract infections caused by macrolide-resistant pathogens. Further studies are needed to elucidate its clinical efficacy against H. influenzae, potential drug interactions, and safety in various subpopulations.

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Synthesis, in vitro and in silico Studies of Naphthalene Pyrazoline Prop-2-en-1-one Derivatives

Asian Journal of Chemistry ◽

10.14233/ajchem.2020.22654 ◽

2020 ◽

Vol 32 (8) ◽

pp. 1849-1856

Author(s):

B. Prabha ◽

C. Raja ◽

S. Nathiya ◽

M.R. Ezhilarasi

Keyword(s):

Binding Affinity ◽

Addition Reaction ◽

Condensation Reaction ◽

Docking Studies ◽

High Drug ◽

In Silico Studies ◽

Drug Score ◽

The Michael Addition ◽

High Inhibition

The synthesized new naphthalene pyrazoline prop-2-en-1-one derivatives (NDPP 1-8) were obtained by the Michael addition reaction of ethyl propanoate, hydrazine hydrate with NPD as a multicomponent scaffold. (E)-1-(naphthalen-3-yl)-3-phenylprop-2-en-1-one (NPD) was formed from 2-acetyl naphthalene and substituted aldehyde via Claisen-Schmidt condensation reaction. The NDPP skeleton structures were confirmed by infrared, 1H & 13C NMR spectral data and elemental analysis. The structure of NDPP compounds was subjected to molecular docking and ADME studies. The result of ADME prediction, compound NDPP 2, which contains electron withdrawing -Cl group has high drug-likeness value 4.21 than the compounds NDPP 4 and 7 which had electron donating CH3 and OCH3 group shows the drug-likeness value 2.62. The NDPP 2 also has high drug score 0.63 than NDPP 4 and NDPP 7 have drug score 0.60 and 0.69, respectively. Docking studies shows that compound NDPP 5 which also contain electron withdrawing NO2 group has good binding affinity value -8.8 Kcal/mol were docked with 1UAG protein. These compounds showed good drug-likeness value 2.25 and drug score 0.65. in vitro Studies have a high inhibition value for the same NO2 substituted derivative. All the compounds have higher binding affinity value than standards binding affinity value.

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Exemplifying the next generation of antibiotic susceptibility intensifiers of phytochemicals by LasR-mediated quorum sensing inhibition

Scientific Reports ◽

10.1038/s41598-021-01845-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Arpit Shukla ◽

Gaurav Shukla ◽

Paritosh Parmar ◽

Baldev Patel ◽

Dweipayan Goswami ◽

...

Keyword(s):

Quorum Sensing ◽

Metabolic Pathways ◽

Single Unit ◽

Antimicrobial Properties ◽

Well Being ◽

Natural Compounds ◽

Human Pathogens ◽

Quorum Sensing Inhibition ◽

In Silico Studies

AbstractThere persists a constant threat from multidrug resistance being acquired by all human pathogens that challenges the well-being of humans. This phenomenon is predominantly led by Pseudomonas aeruginosa which is already resistant to the current generations of antibiotic by altering its metabolic pathways to survive. Specifically for this microbe the phenomenon of quorum sensing (QS) plays a crucial role in acquiring virulence and pathogenicity. QS is simply the cross talk between the bacterial community driven by signals that bind to receptors, enabling the entire bacterial microcosm to function as a single unit which has led to control P. aeruginosa cumbersome even in presence of antibiotics. Inhibition of QS can, therefore, be of a significant importance to curb such virulent and pathogenic strains of P. aeruginosa. Natural compounds are well known for their antimicrobial properties, of which, information on their mode of action is scarce. There can be many antimicrobial phytochemicals that act by hindering QS-pathways. The rationale of the current study is to identify such natural compounds that can inhibit QS in P. aeruginosa driven by LasR, PhzR, and RhlR dependent pathways. To achieve this rationale, in silico studies were first performed to identify such natural compounds which were then validated by in vitro experiments. Gingerol and Curcumin were identified as QS-antagonists (QSA) which could further suppress the production of biofilm, EPS, pyocyanin, and rhamnolipid along with improving the susceptibility to antibiotics.

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Predominance of Bacterial Flora Causing Lower Respiratory Tract Infections Following Tracheostomy in Patients of Chettinad Hospital & Research Institute, Chennai, India

Journal of Evolution of Medical and Dental Sciences ◽

10.14260/jemds/2021/606 ◽

2021 ◽

Vol 10 (35) ◽

pp. 2964-2968

Author(s):

Swetha Thirumurthi ◽

Priya Kanagamuthu ◽

Rajasekaran Srinivasan ◽

Bhalaji Dhanasekaran

Keyword(s):

Pseudomonas Aeruginosa ◽

Respiratory Tract ◽

Lower Respiratory Tract ◽

Respiratory Tract Infections ◽

Antibiotic Sensitivity ◽

Klebsiella Pneumonia ◽

Lower Respiratory Tract Infections ◽

Empirical Antibiotics ◽

Tract Infections ◽

Research Institute

BACKGROUND The term tracheostomy refers to forming an opening in the trachea.1,2 Its advantages include easy and direct access to lower respiratory tract, reduced risk of aspiration, faster weaning from ventilation support and improved physical and psychological comfort. But a common problem in tracheostomised patients is increased risk of colonisation of lower respiratory tract by exogenous bacteria because of direct exposure.1,3 This study was done to recognise pathogens in tracheal secretions collected from tracheostomised patients and their antibiotic sensitivity to treat them with appropriate antibiotics. METHODS This prospective study was done in 138 tracheostomised patients from October 2020 to March 2021 in intensive care unit (ICU) of Chettinad Hospital and Research Institute. Under sterile aseptic precautions, Day 0 and Day 7 cultures posttracheostomy was obtained and their antibiotic sensitivity was studied. Data was analysed using Statistical Package for Social Sciences (SPSS version 19) and presented in proportion, mean and standard deviation (Descriptive statistics). RESULTS In this study, of the 56 cases who had growth in their culture and sensitivity reports on day 0, the most common organism was Pseudomonas aeruginosa (33.9 %) sensitive to imipenem (94.7 %) followed by klebsiella (25 %) sensitive to teicoplanin, vancomycin, amikacin, cefoperazone/tazobactam, linezolid and piperacillin/tazobactam. On day 7, the growth of organisms isolated in tracheal culture got reduced from 56 cases to 16 cases. The prevalence of Pseudomonas reduced to 18.8 % in day 7 whereas Klebsiella pneumonia and Acinetobacter remained almost same from day 0 to day 7. CONCLUSIONS This study concludes the predominant pathogen as Pseudomonas aeruginosa with sensitivity to imipenem followed by Klebsiella with sensitivity to teicoplanin, vancomycin, amikacin, cefoperazone/tazobactam, linezolid and piperacillin/tazobactam on day 0 with reduction in the number of organisms on day 7 due to the fact that all our patients were admitted in ICU several days prior to tracheostomy and were started on antibiotics soon after admission as per choice of the treating physician. Hence, a clear understanding of bacterial colonisation post tracheostomy and its change in course is essential for timely intervention with empirical antibiotics for reducing the incidence of lower respiratory tract infections after tracheostomy in future. KEY WORDS Tracheostomy, Lower Respiratory Tract Infections, Pseudomonas Aeruginosa, Empirical Antibiotics.

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