scholarly journals Screening of FDA-Approved Drugs Using a 384-Well Plate-Based Biofilm Platform: The Case of Fingolimod

2020 ◽  
Vol 8 (11) ◽  
pp. 1834
Author(s):  
Shella Gilbert-Girard ◽  
Kirsi Savijoki ◽  
Jari Yli-Kauhaluoma ◽  
Adyary Fallarero
Keyword(s):  
Biofilm Formation ◽  
Inhibitory Concentration ◽  
Bacterial Count ◽  
Culture Collection ◽  
Gram Negative Bacteria ◽  
Approved Drugs ◽  
Time Kill ◽  
Fda Approved Drugs ◽  
Modest Activity

In an effort to find new repurposed antibacterial compounds, we performed the screening of an FDA-approved compounds library against Staphylococcus aureus American Type Culture Collection (ATCC) 25923. Compounds were evaluated for their capacity to prevent both planktonic growth and biofilm formation as well as to disrupt pre-formed biofilms. One of the identified initial hits was fingolimod (FTY720), an immunomodulator approved for the treatment of multiple sclerosis, which was then selected for follow-up studies. Fingolimod displayed a potent activity against S. aureus and S. epidermidis with a minimum inhibitory concentration (MIC) within the range of 12–15 µM at which concentration killing of all the bacteria was confirmed. A time–kill kinetic study revealed that fingolimod started to drastically reduce the viable bacterial count within two hours and we showed that no resistance developed against this compound for up to 20 days. Fingolimod also displayed a high activity against Acinetobacter baumannii (MIC 25 µM) as well as a modest activity against Escherichia coli and Pseudomonas aeruginosa. In addition, fingolimod inhibited quorum sensing in Chromobacterium violaceum and might therefore target this signaling pathway in certain Gram-negative bacteria. In conclusion, we present the identification of fingolimod from a compound library and its evaluation as a potential repurposed antibacterial compound.

scholarly journals Antimicrobial and antibiofilm properties of essential oils from Piper marginatum Jacq.

2021 ◽  
Vol 10 (11) ◽  
pp. e514101119967
Author(s):  
Ana Lúcia Mendes dos Santos ◽  
Filipe Augusto Matos Araújo ◽  
Érika da Silva Matisui ◽  
Luiz Antonio Mendonça Alves da Costa ◽  
Alexandre José Macêdo ◽  
...  
Keyword(s):  
Essential Oils ◽  
Biofilm Formation ◽  
Pathogenic Bacteria ◽  
Inhibitory Concentration ◽  
Folk Medicine ◽  
Gram Negative Bacteria ◽  
Biofilm Inhibition ◽  
Future Developments ◽  
Phytochemical Constituents ◽  
Amazonian Region

A low shrub growing in the Amazonian region, Piper marginatum Jacq. has been related to the treatment of a disease variety in folk medicine, however, still lacking scientific support. This study aimed to describe the composition of essential oils obtained from leaves (EOL) and branches (EOB) of P. marginatum and their antimicrobial effects on six relevant pathogenic bacteria. A combination of GC-FID and GC-MS was used to identify the phytochemical constituents. As antimicrobial assays, the oils were screened at the minimum inhibitory concentration (MIC) of 3 µg/ml for planktonic and biofilm inhibition. EOL revealed the presence of trans–nerolidol, o–cymene, spathulenol, elemicin, and α–copaene, while EOB composition was mainly of myristicin, trans-caryophyllene, trans-nerolidol, caryophyllene oxide, α–copaene, γ–muurolene and spathulenol. The strongest inhibition of planktonic growth was achieved against Pseudomonas aeruginosa (EOB) and Escherichia coli (EOB). Overall, Gram negative bacteria were more sensitive to both EOB/EOL showing less ability of growth and biofilm formation. The Gram-positive strains seemed to react to the essential oils by massive adhesion. Our results corroborate the relevance of Piperaceae and indicate the possible use of P. marginatum in future developments of antimicrobials.

scholarly journals A Drug Repositioning Approach Reveals that Streptococcus mutans Is Susceptible to a Diverse Range of Established Antimicrobials and Nonantibiotics

2017 ◽  
Vol 62 (1) ◽  
Author(s):  
S. Saputo ◽  
R. C. Faustoferri ◽  
R. G. Quivey
Keyword(s):  
Streptococcus Mutans ◽  
Biofilm Formation ◽  
Drug Repositioning ◽  
Drug Screen ◽  
Biofilm Inhibition ◽  
Diverse Range ◽  
Content Type ◽  
Multispecies Biofilm ◽  
Approved Drugs ◽  
Fda Approved Drugs

ABSTRACT Streptococcus mutans is the primary causative agent of dental caries and contributes to the multispecies biofilm known as dental plaque. An adenylate kinase-based assay was optimized for S. mutans to detect cell lysis when exposed to the Selleck library (Selleck Chemical, Houston, TX) of 853 FDA-approved drugs in, to our knowledge, the first high-throughput drug screen in S. mutans. We found 126 drugs with activity against S. mutans planktonic cultures, and they were classified into six categories: antibacterials (61), antineoplastics (23), ion channel effectors (9), other antimicrobials (7), antifungals (6), and other (20). These drugs were also tested for activity against S. mutans biofilm cultures, and 24 compounds were found to inhibit biofilm formation, 6 killed preexisting biofilms, 84 exhibited biofilm inhibition and killing activity, and 12 had no activity against biofilms. The activities of 9 selected compounds that exhibited antimicrobial activity were further characterized for their activity against S. mutans planktonic and biofilm cultures. Together, our results suggest that S. mutans exhibits a susceptibility profile to a diverse array of established and novel antibacterials.

scholarly journals Potential RNA-dependent RNA polymerase inhibitors as prospective therapeutics against SARS-CoV-2

2020 ◽  
Vol 69 (6) ◽  
pp. 864-873 ◽  
Author(s):  
Rudramani Pokhrel ◽  
Prem Chapagain ◽  
Jessica Siltberg-Liberles
Keyword(s):  
Rna Polymerase ◽  
In Silico ◽  
Species Barrier ◽  
Rna Dependent Rna Polymerase ◽  
Virtual Screen ◽  
The Us ◽  
Approved Drugs ◽  
Dynamics Simulations ◽  
Fda Approved Drugs

Introduction. The emergence of SARS-CoV-2 has taken humanity off guard. Following an outbreak of SARS-CoV in 2002, and MERS-CoV about 10 years later, SARS-CoV-2 is the third coronavirus in less than 20 years to cross the species barrier and start spreading by human-to-human transmission. It is the most infectious of the three, currently causing the COVID-19 pandemic. No treatment has been approved for COVID-19. We previously proposed targets that can serve as binding sites for antiviral drugs for multiple coronaviruses, and here we set out to find current drugs that can be repurposed as COVID-19 therapeutics. Aim. To identify drugs against COVID-19, we performed an in silico virtual screen with the US Food and Drug Administration (FDA)-approved drugs targeting the RNA-dependent RNA polymerase (RdRP), a critical enzyme for coronavirus replication. Methodology. Initially, no RdRP structure of SARS-CoV-2 was available. We performed basic sequence and structural analysis to determine if RdRP from SARS-CoV was a suitable replacement. We performed molecular dynamics simulations to generate multiple starting conformations that were used for the in silico virtual screen. During this work, a structure of RdRP from SARS-CoV-2 became available and was also included in the in silico virtual screen. Results. The virtual screen identified several drugs predicted to bind in the conserved RNA tunnel of RdRP, where many of the proposed targets were located. Among these candidates, quinupristin is particularly interesting because it is expected to bind across the RNA tunnel, blocking access from both sides and suggesting that it has the potential to arrest viral replication by preventing viral RNA synthesis. Quinupristin is an antibiotic that has been in clinical use for two decades and is known to cause relatively minor side effects. Conclusion. Quinupristin represents a potential anti-SARS-CoV-2 therapeutic. At present, we have no evidence that this drug is effective against SARS-CoV-2 but expect that the biomedical community will expeditiously follow up on our in silico findings.

scholarly journals Broad anti-coronaviral activity of FDA approved drugs against SARS-CoV-2 in vitro and SARS-CoV in vivo

2020 ◽  
Author(s):  
Stuart Weston ◽  
Christopher M. Coleman ◽  
Rob Haupt ◽  
James Logue ◽  
Krystal Matthews ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Rapid Development ◽  
Drug Repurposing ◽  
Ic50 Values ◽  
Human Use ◽  
Approved Drugs ◽  
Fda Approved Drugs

AbstractSARS-CoV-2 emerged in China at the end of 2019 and has rapidly become a pandemic with roughly 2.7 million recorded COVID-19 cases and greater than 189,000 recorded deaths by April 23rd, 2020 (www.WHO.org). There are no FDA approved antivirals or vaccines for any coronavirus, including SARS-CoV-2. Current treatments for COVID-19 are limited to supportive therapies and off-label use of FDA approved drugs. Rapid development and human testing of potential antivirals is greatly needed. A quick way to test compounds with potential antiviral activity is through drug repurposing. Numerous drugs are already approved for human use and subsequently there is a good understanding of their safety profiles and potential side effects, making them easier to fast-track to clinical studies in COVID-19 patients. Here, we present data on the antiviral activity of 20 FDA approved drugs against SARS-CoV-2 that also inhibit SARS-CoV and MERS-CoV. We found that 17 of these inhibit SARS-CoV-2 at a range of IC50 values at non-cytotoxic concentrations. We directly follow up with seven of these to demonstrate all are capable of inhibiting infectious SARS-CoV-2 production. Moreover, we have evaluated two of these, chloroquine and chlorpromazine, in vivo using a mouse-adapted SARS-CoV model and found both drugs protect mice from clinical disease.

scholarly journals Influence of Gallic Acid and Thai Culinary Essential Oils on Antibacterial Activity of Nisin against Streptococcus mutans

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Pimsumon Jiamboonsri ◽  
Pimpikar Kanchanadumkerng
Keyword(s):  
Essential Oils ◽  
Gallic Acid ◽  
Streptococcus Mutans ◽  
Biofilm Formation ◽  
Inhibitory Concentration ◽  
Microdilution Method ◽  
Broth Microdilution Method ◽  
Life Threatening ◽  
Oral Pathogens ◽  
Time Kill

Streptococcus mutans is a well-known oral pathogen commonly associated with a normal dental problem and life-threatening infection. A bacteriocin nisin and the plant-derived compounds including gallic acid (GA) and Thai culinary essential oils (EOs) have been reported to have activity against oral pathogens. However, their synergistic interaction against S. mutans has not been explored. The purposes of this study were primarily to investigate anti-S. mutans properties and the antibiofilm formation of nisin, GA, and five EOs by using the broth microdilution method. Besides, the morphological change, killing rate, and antibacterial synergism were determined by scanning electron microscopy (SEM), time-kill assay, and checkerboard method, respectively. The results demonstrated that kaffir lime leaf (KLL) oil, lemongrass (LG) oil, and GA showed a potent anti-S. mutans activity and inhibited biofilm formation with the possible mechanism targeted on the cell membrane. Additionally, KLL oil revealed anti-S. mutans synergism with GA, LG oil, and chlorhexidine with the fractional inhibitory concentration (FIC) indexes ≤ 0.5. Interestingly, GA displayed a high potential to enhance anti-S. mutans activity of nisin by lowering the minimum inhibitory concentrations (MICs) to at least 8-fold in a bacteriostatic manner. These results suggest that GA and KLL oil may be potentially used as an adjunctive therapy along with nisin and chlorhexidine to control S. mutans infection.

scholarly journals Ceftazidime Is a Potential Drug to Inhibit SARS-CoV-2 Infection In Vitro by Blocking Spike Protein-ACE2 Interaction

2020 ◽  
Author(s):  
ChangDong Lin ◽  
Yue Li ◽  
MengYa Yuan ◽  
MengWen Huang ◽  
Cui Liu ◽  
...  
Keyword(s):  
Small Molecules ◽  
High Throughput Screening ◽  
Inhibitory Concentration ◽  
Cell Entry ◽  
Host Cells ◽  
First Line ◽  
Angiotensin Converting Enzyme 2 ◽  
Approved Drugs ◽  
Fda Approved Drugs

SUMMARYCoronavirus Disease 2019 (COVID-19) spreads globally as a sever pandemic, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Cell entry of SARS-CoV-2 mainly depends on binding of the viral spike (S) proteins to angiotensin converting enzyme 2 (ACE2) on host cells. Therefore, repurposing of known drugs to inhibit S protein-ACE2 interaction could be a quick way to develop effective therapy for COVID-19. Using a high-throughput screening system to investigate the interaction between spike receptor binding domain (S-RBD) and ACE2 extracellular domain, we screened 3581 FDA-approved drugs and natural small molecules and identified ceftazidime as a potent compound to inhibit S-RBD–ACE2 interaction by binding to S-RBD. In addition to significantly inhibit S-RBD binding to HPAEpiC cells, ceftazidime efficiently prevented SARS-CoV-2 pseudovirus to infect ACE2-expressing 293T cells. The inhibitory concentration (IC50) was 113.2 μM, which is far below the blood concentration (over 300 μM) of ceftazidime in patients when clinically treated with recommended dose. Notably, ceftazidime is a drug clinically used for the treatment of pneumonia with minimal side effects compared with other antiviral drugs. Thus, ceftazidime has both anti-bacterial and anti-SARS-CoV-2 effects, which should be the first-line antibiotics used for the clinical treatment of COVID-19.

scholarly journals Role of PBPD1 in Stimulation of Listeria monocytogenes Biofilm Formation by Subminimal Inhibitory β-Lactam Concentrations

2014 ◽  
Vol 58 (11) ◽  
pp. 6508-6517 ◽  
Author(s):  
Uyen T. Nguyen ◽  
Hanjeong Harvey ◽  
Andrew J. Hogan ◽  
Alexandria C. F. Afonso ◽  
Gerard D. Wright ◽  
...  
Keyword(s):  
Listeria Monocytogenes ◽  
Biofilm Formation ◽  
Regulatory System ◽  
Content Type ◽  
Food Borne ◽  
Approved Drugs ◽  
Biofilm Development ◽  
Fda Approved Drugs ◽  
Stimulation Of

ABSTRACTDisinfectant-tolerantListeria monocytogenesbiofilms can colonize surfaces that come into contact with food, leading to contamination and, potentially, food-borne illnesses. To better understand the process ofL. monocytogenesbiofilm formation and dispersal, we screened 1,120 off-patent FDA-approved drugs and identified several that modulateListeriabiofilm development. Among the hits were more than 30 β-lactam antibiotics, with effects ranging from inhibiting (≤50%) to stimulating (≥200%) biofilm formation compared to control. Most β-lactams also dispersed a substantial proportion of established biofilms. This phenotype did not necessarily involve killing, as >50% dispersal could be achieved with concentrations as low as 1/20 of the MIC of some cephalosporins. Penicillin-binding protein (PBP) profiling using a fluorescent penicillin analogue showed similar inhibition patterns for most β-lactams, except that biofilm-stimulatory drugs did not bind PBPD1, a low-molecular-weightd,d-carboxypeptidase. Compared to the wild type, apbpD1mutant had an attenuated biofilm response to stimulatory β-lactams. The cephalosporin-responsive CesRK two-component regulatory system, whose regulon includes PBPs, was not required for the response. The requirement for PBPD1 activity for β-lactam stimulation ofL. monocytogenesbiofilms shows that the specific set of PBPs that are inactivated by a particular drug dictates whether a protective biofilm response is provoked.

Synthesis of new Enrofloxacin Derivatives as Potential Antibiofilm Drugs Against Staphylococcus Aureus and Klebsiella Pneumoniae

2020 ◽  
Vol 17 (1) ◽  
pp. 85-96
Author(s):  
Hina Siddiqui ◽  
Haroon M. Haniffa ◽  
Ayaz Ahmed ◽  
Muhammad I. Choudhary
Keyword(s):  
Staphylococcus Aureus ◽  
Biofilm Formation ◽  
Aromatic Amines ◽  
Normal Cell ◽  
Mouse Fibroblast ◽  
Food Industries ◽  
Control Drug ◽  
Bactericidal Properties ◽  
Approved Drugs ◽  
Fda Approved Drugs

Background: The antimicrobial resistance due to biofilm formation among bacteria is a significant problem in the healthcare and food industries. Objective: The current study describes the synthesis of enrofloxacin derivatives 2-17, and the evaluation of their anti-bacterial and anti-biofilm activities. Methods: Compounds 2-17 were synthesized through the acylation of enrofloxacin with thionyl chloride, followed by reaction with different aromatic amines. The new analogues identified among the sixteen compounds were 2-7, 11, 14, and 17. Results: Compound 2 appeared to be effective against pathogens S. aureus as well as K. pneumonia, whereas, compound 11 was found active against K. pneumonia only. Compound 2 inhibited >75% biofilm formation of S. aureus at 20 μg/mL and K. pneumonia at 10 μg/mL concentrations. These doses are far below the bactericidal concentration of compound 2, suggesting the anti-virulence mechanism of these compounds. Compound 11 inhibited 60% biofilm formation of K. pneumoniae at 70 μg/mL concentration. Compound 5 inhibited the biofilm of K. pneumoniae at 62 μg/mL concentration but also had bactericidal properties at this concentration. Interestingly, compound 2 eradicated the preformed biofilm of both the pathogens at much lower doses as compared to control drug, gentamycin and substrate, enrofloxacin. Cytotoxicity of compounds 2–17 was checked by a standard method using 3T3 normal cell lines (mouse fibroblast), all compounds were found to be noncytotoxic. Conclusion: These compounds can be used alone or with FDA approved drugs to overcome biofilm related K. pneumoniae and S. aureus infections.

scholarly journals Simultaneous Hydrodistillation-Steam Distillation of Rosmarinus officinalis, Lavandula angustifolia and Citrus aurantium from Morocco, Major Terpenes: Impact on Biological Activities

Molecules ◽  
2021 ◽  
Vol 26 (18) ◽  
pp. 5452
Author(s):  
Sara El Kharraf ◽  
Maria Leonor Faleiro ◽  
Farah Abdellah ◽  
Soukaïna El-Guendouz ◽  
El Mestafa El Hadrami ◽  
...  
Keyword(s):  
Biofilm Formation ◽  
Steam Distillation ◽  
Inhibitory Concentration ◽  
Biological Activities ◽  
Extraction Process ◽  
Antibiofilm Activity ◽  
Gram Negative Bacteria ◽  
Linalyl Acetate ◽  
Food Industries ◽  
The Individual

Interest in the use of essential oils (EOs) in the biomedical and food industries have seen growing over the last decades due to their richness in bioactive compounds. The challenges in developing an EO extraction process that assure an efficient levels of monoterpenes with impact on biological activities have driven the present study, in which the EO extraction process of rosemary, lavender and citrus was performed by simultaneous hydrodistillation–steam distillation, and the influence of EO composition on biological activities, namely antioxidant, anti-inflammatory, antidiabetic, anti-acetylcholinesterase, anti-tyrosinase, antibacterial, and antibiofilm activity, were evaluated. The EO yields of combinations were generally higher than the individual plants (R. officinalis (Ro), L. angustifolia (La), and C. aurantium (Ca)) extracted by the conventional hydrodistillation. The EOs obtained by this process generally had a better capacity for scavenging the free radicals, inhibiting α-glucosidase, and acetylcholinesterase activities than the individual EOs. The combination of EOs did not improve the ability for scavenging peroxide hydrogen or the capacity for inhibiting lipoxygenase activity. The antioxidant activity or the enzyme inhibition activity could not only be attributed to their major compounds because they presented lower activities than the EOs. The chemical composition of the combination Ro:La:Ca, at the ratio 1/6:1/6:2/3, was enriched in 1,8-cineole, linalool, and linalyl acetate and resulted in lower MIC values for all tested strains in comparison with the ratio 1/6:2/3:1/6 that was deprived on those components. The biofilm formation of Gram positive and Gram negative bacteria was impaired by the combination Ro:La:Ca at a sub-inhibitory concentration.

Effect of piperacillin on morphology and viability of gram-negative bacteria

1984 ◽  
Vol 42 ◽  
pp. 218-219
Author(s):  
R. H. Liss
Keyword(s):  
Inhibitory Concentration ◽  
Cytoplasmic Membrane ◽  
Drug Binding ◽  
Gram Negative Bacteria ◽  
Bacterial Cells ◽  
Drug Induced ◽  
Penicillin Binding Proteins ◽  
Lactam Antibiotic ◽  
Drug Free ◽  
Tube Dilution

Piperacillip (PIP) is b-[D(-)-α-(4-ethy1-2,3-dioxo-l-piperzinylcar-bonylamino)-α-phenylacetamido]-penicillanate. The broad spectrum semisynthetic β-lactam antibiotic is believed to effect bactericidal activity through its affinity for penicillin-binding proteins (PBPs), enzymes on the bacterial cytoplasmic membrane that control elongation and septation during cell growth and division. The purpose of this study was to correlate penetration and binding of 14C-PIP in bacterial cells with drug-induced lethal changes assessed by microscopic, microbiologic and biochemical methods.The bacteria used were clinical isolates of Escherichia coli and Pseudomonas aeruginosa (Figure 1). Sensitivity to the drug was determined by serial tube dilution in Trypticase Soy Broth (BBL) at an inoculum of 104 organisms/ml; the minimum inhibitory concentration of piperacillin for both bacteria was 1 μg/ml. To assess drug binding to PBPs, the bacteria were incubated with 14C-PIP (5 μg/0.09 μCi/ml); controls, in drug-free medium.

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