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Novel antimicrobials are urgently needed to combat drug-resistant bacteria and to overcome the inherent difficulties in treating biofilm-associated infections. Studying plants and other natural materials used in historical infection remedies may enable further discoveries to help fill the antibiotic discovery gap. We previously reconstructed a 1,00...
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... data are supplied in the Data Supplement. (B) Six carriage isolates of S. aureus, and six isolates from a chronic post-surgical wound (detailed in Table 4), were grown in the synthetic wound biofilm model and treated with ESO, ESL or water (n = 3 per treatment). Each strain grew to different densities in untreated wounds (range approx. ...Citations
... Biofilm-embedded bacteria can be more than 1000X more resistant to systemic antibiotics than planktonic bacteria [13], forcing physicians to administer broad-spectrum antibiotics systemically at significantly higher concentrations than typical therapeutic dosages. The high concentrations of systemic antibiotics may increase the risk of deleterious side effects and further exacerbate the antibiotic-resistance crisis [14]. Debridement of biofilms effectively reduces the bacterial load temporarily; however, biofilm regrowth is remarkably rapid even in combination with systemic antibiotics [15]. ...
The complexity of chronic wounds creates difficulty in effective treatments, leading to prolonged care and significant morbidity. Additionally, these wounds are incredibly prone to bacterial biofilm development, further complicating treatment. The current standard treatment of colonized superficial wounds, debridement with intermittent systemic antibiotics, can lead to systemic side-effects and often fails to directly target the bacterial biofilm. Furthermore, standard of care dressings do not directly provide adequate antimicrobial properties. This study aims to assess the capacity of human-derived collagen hydrogel to provide sustained antibiotic release to disrupt bacterial biofilms and decrease bacterial load while maintaining host cell viability and scaffold integrity. Human collagen harvested from flexor tendons underwent processing to yield a gellable liquid, and subsequently was combined with varying concentrations of gentamicin (50–500 mg/L) or clindamycin (10–100 mg/L). The elution kinetics of antibiotics from the hydrogel were analyzed using liquid chromatography-mass spectrometry. The gel was used to topically treat Methicillin-resistant Staphylococcus aureus (MRSA) and Clostridium perfringens in established Kirby-Bauer and Crystal Violet models to assess the efficacy of bacterial inhibition. 2D mammalian cell monolayers were topically treated, and cell death was quantified to assess cytotoxicity. Bacteria-enhanced in vitro scratch assays were treated with antibiotic-embedded hydrogel and imaged over time to assess cell death and mobility. Collagen hydrogel embedded with antibiotics (cHG+abx) demonstrated sustained antibiotic release for up to 48 hours with successful inhibition of both MRSA and C . perfringens biofilms, while remaining bioactive up to 72 hours. Administration of cHG+abx with antibiotic concentrations up to 100X minimum inhibitory concentration was found to be non-toxic and facilitated mammalian cell migration in an in vitro scratch model. Collagen hydrogel is a promising pharmaceutical delivery vehicle that allows for safe, precise bacterial targeting for effective bacterial inhibition in a pro-regenerative scaffold.
... Numerous host-mimicking growth media have been developed to mimic the nutrition of different host environments, allowing for monitoring of how these growth environments alter the phenotypes of pathogens (16). These include artificial urine (17), artificial saliva (18), and synthetic wound fluid (19), for the modelling of urinary tract infections (20), periodontitis (21), and chronic wound infections (22), respectively. For modelling the pulmonary environment, studies investigating both chronic and acute infection of the cystic fibrosis (CF) lung dominate, with a large array of CF sputum-mimicking media described (16,(23)(24)(25)(26)(27)(28)(29)(30)(31). ...
Growth environment greatly alters many facets of pathogen physiology, including pathogenesis and antimicrobial tolerance. The importance of host-mimicking environments for attaining an accurate picture of pathogen behaviour is widely recognised. Whilst this recognition has translated into the extensive development of artificial cystic fibrosis (CF) sputum medium, attempts to mimic the growth environment in other respiratory disease states have been completely neglected. The composition of the airway surface liquid (ASL) in different pulmonary diseases is far less well characterised than CF sputum, making it very difficult for researchers to model these infection environments. In this review we discuss the components of human ASL, how different lung pathologies affect ASL composition, and how different pathogens interact with these components. This will provide researchers interested in mimicking different respiratory environments with the information necessary to design a host-mimicking medium, allowing for better understanding of how to treat pathogens causing infection in these environments.
... The goal was to study the medical approaches of past physicians and to demonstrate the efficacy of an ancient remedy. By faithfully reproducing this remedy, the authors demonstrated that it drastically limited the growth of bacterial pathogens like Staphylococcus aureus, Pseudomonas aeruginosa or Neisseria gonorrhoeae in vitro, and/or on a mouse model of eye infection, with a reasonable safety profile [41][42][43][44] . ...
The proliferation and prevalence of antibiotic-resistant bacteria despite modern medicine is considered as one of the most alarming threats to global health. The fear that antibiotics that work today might not work tomorrow makes it imperative to search and develop novel drugs or therapeutic strategies to fight against micro-organisms resistant to our current approaches. From many centuries, people have sought solutions to combat infections and proposed countless remedies, traces of which can be found in manuscripts preserved over the past centuries. The re-examination and exploitation of these ancient remedies might be a key to a vast pool of potential therapeutic strategies or drug candidates against antibiotic-resistant pathogens. This, however, would first require the consideration of these ancient solutions as scientifically pertinent leads for new therapies. The aim of this review is to highlight arguments in favor of a rationality in the scientific approach of these past physicians as well as of a medicinal interest in studying these ancient pharmacopeias. To narrow the scope of our research, we focused on the Arab Medieval Golden Medical Age, which inspired occidental medicine hundreds of years after its preeminence. We further highlight the possibility of integrating this knowledge into innovative, modern therapeutic approaches.
... Medicinal plant, however, shows promising effect in mitigating, if not eradicating the problems of antibiotic resistance. Unlike conventional medicines that microbes find easy to develop resistance to due to a single active ingredient for the same therapeutic target, herbal medicine uses a combination of efficacious natural active ingredients to breakdown the cell wall and cell membrane of microorganisms, which can lead to the release of cellular contents, protein binding domain disruption, enzyme inactivation, and ultimately leading to cell death 8,9 . More specifically, a 1000year-old antimicrobial remedy was formulated from Bald Leechbook using the ancient's technique and found to be more effective than conventional drug, vancomycin, against methicillin-resistant S. aureus 10 . ...
... Moreover, medicinal plants continue to enjoy human patronage because they are cheap, readily available and free from side effects often associated with conventional antibiotics 11 . Antimicrobial activities of useful plants vary: the majority act in synergy, reducing the side effect of synthetic drugs while others act as quorum quenchers 9,12 . Lawsonia inermis L. (synonym Lawsonia alba), is the sole species of the genus Lawsonia belonging to the family Lythraceae 13 . ...
... The variation in the activity of crude extracts is probably due to the different solvents used as well as plant parts that yield varieties of bioactive compounds. Many previous studies indicated that medicinal plant extract contains several phytochemicals that synergistically show remarkable antimicrobial properties against MDR organisms 9,10,21,34,51 . This might be because of the holistic formation of these complex bioactive compounds that synergistically modulate multiple targets to produce overall inhibitory actions 52 . ...
Objective: Majority of the current antibiotics have become less effective due to widespread of multidrug-resistant microorganisms. Medicinal plants are promising candidates that could be used to manage this menace. Therefore, phytochemical, toxicological and antimicrobial potentiality of Lawsonia inermis extracts against MDR clinical bacteria were carried out. Material-Method: Henna leaf and seed were extracted by cold maceration technique using methanol and water and screened phytochemically. Eight MDR isolates, four of which are ESβL-producers were used for this study. In vitro antimicrobial efficacy and quantitative antimicrobial potency of extracts were estimated. MIC and MBC were determined using broth macrodilution technique. Cytotoxicity test was conducted using brine shrimp lethality assay and LC50 was determined. Results: The findings of this study revealed that aqueous leaf extract possesses maximum percentage yield of 25.58%. Tannins and phenolic compounds were detected in all extracts, while steroid was absent. Methanol seed extract showed the highest antimicrobial efficacy against all bacteria with 100 percent activity. The highest and lowest zones of inhibition were recorded at 30.0±0.00 and 10.0±0.00 mm, respectively. The zones of inhibition of extracts differed significantly. All extracts displayed highest activity index against the ESβL-producing Enterobacter aerogenes 196 that was isolated from wound with highest value at 4.28. Pseudomonas aeruginosa U109 showed maximum susceptibility index (93.75%); majority of MIC values recorded were within the range of 1.95-62.5 mg/mL. Cytotoxicity test of methanol and aqueous extracts displayed 10001000, respectively. Conclusion: Findings from this study elucidate the efficacy of Lawsonia inermis as a potential remedy to manage MDR-related infectious bacteria.
... Thus planktonic testing misses important synergistic interactions between ingredients in the recipe that are necessary to kill biofilms. 2,12,13,40,42 This is a strong case for incorporating interdisciplinary aims to guide scientific practice and improve on standard protocols. ...
Interdisciplinary collaboration is regarded as a desirable way of researching and, in some instances, even a requirement for academic teams and funding proposals. This paper explores the possibilities, but also the problems, of collaboration between different disciplines through a case study of the Ancientbiotics team. This team explores the potential of natural products contained in historical medical recipes. The search for clinically useful natural products in unusual places, such as historical medical practices, is a well-established endeavor in the scientific disciplines. The Ancientbiotics collaboration, largely based across UK institutions, takes this path a step forward in combining modern scientific knowledge of natural products with expertise from humanities to identify ingredient combinations. After 7 years of practice, the research has produced a variety of outcomes. This perspective will explore how the team worked within an interdisciplinary framework to advance investigation and application of historical medical recipes.
... Our team has extensively tested a remedy for eye infection from Bald's Leechbook for its potential to kill pathogenic bacteria grown as biofilms in conditions mimicking soft-tissue chronic wounds. We demonstrated that a reconstruction of this NP cocktail, known as Bald's eyesalve, possesses remarkable ability to kill biofilms of Staphylococcus aureus, Acinetobacter baumannii or Streptococcus pyogenes in an ex vivo wound model, and to kill bacteria in biofilms of methicillin-resistant S. aureus in biopsies taken from mouse chronic wound infections 26,27 . The eyesalve can kill other Gram-positive and Gram-negative wound pathogens when grown planktonically 26 . ...
... We demonstrated that a reconstruction of this NP cocktail, known as Bald's eyesalve, possesses remarkable ability to kill biofilms of Staphylococcus aureus, Acinetobacter baumannii or Streptococcus pyogenes in an ex vivo wound model, and to kill bacteria in biofilms of methicillin-resistant S. aureus in biopsies taken from mouse chronic wound infections 26,27 . The eyesalve can kill other Gram-positive and Gram-negative wound pathogens when grown planktonically 26 . It may thus have capacity to aid in biofilm clearance of these species when combined with antibiotics or adjuvants that enhance penetration through the biofilm matrix. ...
... Bald's eyesalve is a preparation of garlic (Allium sativum), onion (A. cepa), wine and bovine bile, and its antibiofilm efficacy relies on the combination of all these constituents 26,27 . Efficacy cannot be attributed to any single ingredient in the cocktail, i.e. the combination and preparation of ingredients generates a cocktail of compounds and/or a novel compound which effectively kills bacteria. ...
New antibiotics are urgently needed to reduce the health burden of antibiotic-resistant bacterial infection. Natural products (NPs) derived from plants and animals are a current focus of research seeking to discover new antibacterial molecules with clinical potential. A cocktail of NPs based on a medieval remedy for eye infection eliminated biofilms of several highly antibiotic-resistant bacterial species in laboratory studies, and had a promising safety profile in vitro and in a mouse model. A necessary prelude to refining this remedy into a defined, synthetic mixture suitable for testing with wound infections is to firstly establish safety when applied to healthy human skin. We aimed to assess skin-related outcomes of the preparation in a sample of healthy volunteers. This prospective, single arm, non-randomised Phase I clinical trial consisted of a single patch test intervention with 48-h follow-up. Volunteers were staff, students and members of the public recruited from the University of Warwick and surrounding locality. Adults aged 18–79 years, with no history of severe immunity-related disease, diabetes, recent infection, or known pregnancy were eligible. A 100 µl application of a filter-sterilised NP mixture, comprising ground garlic, onion, white wine and bovine bile, was applied to skin on the upper arm and covered with a dressing. The primary outcome was skin-related adverse events over 48 h. Digital photographs were captured where bothersome, salve-related events were reported. 109 volunteers, aged 18–77 years, were recruited between June and July 2021. Sample mean age was 37.6 (SD 16.1) years, and 63 (58%) participants were female. Outcome data were obtained for 106/109 (97%); two participants were lost to follow-up and one removed the skin patch after nine hours due to a bothersome garlic odour. Twenty-one (19.8%) participants reported any patch-test related sign or symptom; of these 14 (13.2%) participants reported minor events related to the salve, including itchiness, redness, or garlic odour. No serious events were reported. We found no evidence of serious skin-related adverse events related to the NP preparation. Trial registration: International Standard Randomised Controlled Trial Number (ISRCTN10773579). Date registered: 08/01/2021.
... The MIC of antibiotics is significant against planktonic microbes but not effective against biofilm microbes [107]. Microbial biofilms can induce several persistent biofilmassociated infections, such as urinary tract infections, middle-ear infections, dental caries, endocarditis, cystic fibrosis, osteomyelitis, and implant-induced infections. ...
Microbial biofilm is an aggregation of microbial species that are either attached to surfaces or organized into an extracellular matrix. Microbes in the form of biofilms are highly resistant to several antimicrobials compared to planktonic microbial cells. Their resistance developing ability is one of the major root causes of antibiotic resistance in health sectors. Therefore, effective antibiofilm compounds are required to treat biofilm-associated health issues. The awareness of biofilm properties, formation, and resistance mechanisms facilitate researchers to design and develop combating strategies. This review highlights biofilm formation, composition, major stability parameters, resistance mechanisms, pathogenicity, combating strategies, and effective biofilm-controlling compounds. The naturally derived products, particularly plants, have demonstrated significant medicinal properties, producing them a practical approach for controlling biofilm-producing microbes. Despite providing effective antibiofilm activities, the plant-derived antimicrobial compounds may face the limitations of less bioavailability and low concentration of bioactive molecules. The microbes-derived and the phytonanotechnology-based antibiofilm compounds are emerging as an effective approach to inhibit and eliminate the biofilm-producing microbes.
... Therefore, many medicines are based on natural products [3] and it is still possible to find novel biologically active substances in complex mixtures as e.g. shown by Furner-Pardoe et al. [4] Thanks to technological developments in the omics disciplines, comprehensive screenings of complex mixtures became more efficiently and faster [5]. One of these technical developments is high-content screening (HCS), a useful tool that for a comprehensive bioactivity analysis. ...
Complex mixtures containing natural products are still an interesting source of novel drug candidates. High content screening (HCS) is a popular tool to screen for such. In particular, multiplexed HCS assays promise comprehensive bioactivity profiles, but generate also high amounts of data. Yet, only some machine learning (ML) applications for data analysis are available and these usually require a profound knowledge of the underlying cell biology. Unfortunately, there are no applications that simply predict if samples are biologically active or not (any kind of bioactivity). Within this work, we benchmark ML algorithms for binary classification, starting with classical ML models, which are the standard classifiers of the scikit-learn library or ensemble models of these classifiers (a total of 92 models tested). Followed by a partial least square regression (PLSR)-based classification (44 tested models in total) and simple artificial neural networks (ANNs) with dense layers (72 tested models in total). In addition, a novelty detection (ND) was examined, which is supposed to handle unknown patterns. For the final analysis the models, with and without upstream ND, were tested with two independent data sets. In our analysis, a stacking model, an ensamble model of class ML algorithms, performed best to predict new and unknown data. ND improved the predictions of the models and was useful to handle unknown patterns. Importantly, the classifier presented here can be easily rebuilt and be adapted to the data and demands of other groups. The hit detector (ND + stacking model) is universal and suitable for a broader application to support the search for new drug candidates.
... Moreover, it would be great to compare the fasting saliva proteome with the non-fasting saliva, and to see if the fasting saliva can be a source of novel peptides that display health benefits (79). This will address the "myth/superstition" in medieval Europe where fasting saliva was used as a medicine (80,81). ...
The aim of this systematic review was to report the impacts of Ramadan intermittent fasting (RIF) on salivary flow-rate (SFR) and metabolic parameters. A thorough literature search was carried out using the databases PubMed and Scopus from their inception up to 15 July 2021. The Boolean connectors used in PubMed were (Saliva [Mesh] AND Fasting [Mesh]). The same keywords were used in Scopus. Inclusion criteria were defined using PICOS. The research included all original studies involving “healthy” adults and published in English. Methodological quality assessment was performed utilizing the Joanna Briggs Institute Critical Appraisal Tool, which allows attributing scores from 1 to 11 to the selected studies. Two authors carried out the literature search, study selection, and data extraction. Differences on issues were resolved by a third author if necessary. The systematic review protocol was registered within the “Open Science Framework” (Doi: 10.17605/OSF.IO/DE7BH). Six articles met the inclusion criteria. All studies were heterogeneous and had a high score of bias and several methodological differences. The following parameters were collected: SFR, melatonin, cortisol, glucose, immunoglobulin A (IgA), uric-acid, alkaline phosphatase (ALP), and aspartate aminotransferase (AST). The SFR decreased by 10% during Ramadan in fasting subjects. The circadian pattern of melatonin remained unchanged during Ramadan, but melatonin levels dropped significantly from baseline. The salivary cortisol levels were unchanged or increased during Ramadan. The salivary glucose levels were decreased. ALP increased significantly, whilst uric-acid and AST decreased significantly. Salivary IgA decreased during the last week of Ramadan. To conclude, there is a trend toward a decrease in SFR and the content of the majority of the biomarkers investigated, with the exception of ALP and uric-acid. These changes cannot be easily attributed to any single factor (hydration status, dietary habits, physical activity, or hygiene habits).
Systematic Review Registration: [https://osf.io/de7bh/], identifier [Doi: 10.17605/OSF.IO/DE7B].
... Indian medicinal and herbal plants act as factories for numerous bioactive phytocompounds that have potentially shown prominence by attacking invasive infections with their antimicrobial activities. Plant extracts from clove, neem, oregano, garlic, turmeric, cinnamon, and many more have previously been proved as an inhibitory and anti-biofilm against A. baumannii and several MDR (Furner-Pardoe et al., 2020;Lu et al., 2018;Tiwari et al., 2017). Phytocompounds are favored over synthetic drugs due to their fewer toxic effects and adverse reactions. ...
Acinetobacter baumannii is a notorious multidrug resistant bacterium responsible for several hospital acquired infections assisted by its capacity to develop biofilms. A. baumannii BfmR (RstA), a response regulator from the BfmR/S two-component signal transduction system, is the major controller of A. baumannii biofilm development and formation. As a result, BfmR represents a novel target for anti-biofilm treatment against A. baumannii. The discovery of the high-resolution crystal structure of BfmR provides a good chance for computational screening of its probable inhibitors. Therefore, in this study we aim to search new, less toxic, and natural BfmR inhibitors from 8450 phytomolecules available in the Indian Medicinal Plants, Phytochemistry and Therapeutic (IMPPAT) database by analyzing molecular docking against BfmR (PDB ID: 6BR7). Out of these 8450 phytomolecules 6742 molecules were successfully docked with BfmR with the docking score range −6.305 kcal/mol to +5.120 kcal/mol. Structure based-molecular docking (SB-MD) and ADMET (absorption, distribution, metabolism, excretion, & toxicity) profile examination revealed that Norepinephrine, Australine, Calystegine B3, 7,7 A-Diepialexine, and Alpha-Methylnoradrenaline phytocompounds strongly binds to the active site residues of BfmR. Furthermore, molecular dynamics simulation (MDS) studies for 100 ns and the binding free energy (MM/GBSA) analysis elucidated the binding mechanism of Calystegine B3, 7,7 A-Diepialexine, and Alpha-Methylnoradrenaline to BfmR. In summary, these phytocompounds seems to have the promising molecules against BfmR, and thus necessitates further verification by both in vitro and in vivo experiments.
• Highlights
• BfmR plays a key role in biofilm development and exopolysaccharide (EPS) synthesis in A. baumannii.
• Computational approach to search for promising BfmR inhibitors from IMPAAT database.
• The lead phytomolecules such as Calystegine B3, 7,7 A-Diepialexine, and Alpha-Methylnoradrenaline displayed significant binding with BfmR active site.
• The outcome of BfmR binding phytomolecules has broadened the scope of hit molecules validation.
Communicated by Ramaswamy H. Sarma
