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1.
Article in English | MEDLINE | ID: mdl-39010826

ABSTRACT

Cystic fibrosis-related diabetes (CFRD), the most common comorbidity in cystic fibrosis (CF), leads to increased mortality by accelerating the decline in lung function. Scnn1b-Tg transgenic mice overexpressing the epithelial sodium channel ß subunit exhibit spontaneous CF-like lung disease, including airway mucus obstruction and chronic inflammation. Here, we established a chronic CFRD-like model utilizing Scnn1b-Tg mice made diabetic by injection of streptozotocin. In Ussing chamber recordings of trachea, Scnn1b-Tg mice exhibited larger amiloride-sensitive currents and forskolin-activated currents, without a difference in ATP-activated currents compared to wildtype (WT) littermates. Both diabetic WT (WT-D) and diabetic Scnn1b-Tg (Scnn1b-Tg-D) mice on the same genetic background exhibited substantially elevated blood glucose at 8 weeks; glucose levels also were elevated in bronchoalveolar lavage fluid (BALF) Bulk lung RNA-seq data showed significant differences between WT-D and Scnn1b-Tg-D mice. Neutrophil counts in BALF were substantially increased in Scnn1b-Tg-D lungs compared to controls (Scnn1b-Tg-con) and compared to WT-D lungs. Lung histology data showed enhanced parenchymal destruction, alveolar wall thickening, and neutrophilic infiltration in Scnn1b-Tg-D mice compared to WT-D mice, consistent with development of a spontaneous lung infection. We intranasally administered Pseudomonas aeruginosa to induce lung infection in these mice for 24 hours, which led to severe lung leukocytic infiltration and an increase in pro-inflammatory cytokine levels in the BALF. In summary, we established a chronic CFRD-like lung mouse model using the Scnn1b-Tg mice. The model can be utilized for future studies toward understanding the mechanisms underlying the lung pathophysiology associated with CFRD and developing novel therapeutics.

2.
Acta Neuropathol Commun ; 9(1): 171, 2021 10 21.
Article in English | MEDLINE | ID: mdl-34674769

ABSTRACT

The extracellular matrix (ECM) of the cerebral vasculature provides a pathway for the flow of interstitial fluid (ISF) and solutes out of the brain by intramural periarterial drainage (IPAD). Failure of IPAD leads to protein elimination failure arteriopathies such as cerebral amyloid angiopathy (CAA). The ECM consists of a complex network of glycoproteins and proteoglycans that form distinct basement membranes (BM) around different vascular cell types. Astrocyte endfeet that are localised against the walls of blood vessels are tethered to these BMs by dystrophin associated protein complex (DPC). Alpha-dystrobrevin (α-DB) is a key dystrophin associated protein within perivascular astrocyte endfeet; its deficiency leads to a reduction in other dystrophin associated proteins, loss of AQP4 and altered ECM. In human dementia cohorts there is a positive correlation between dystrobrevin gene expression and CAA. In the present study, we test the hypotheses that (a) the positive correlation between dystrobrevin gene expression and CAA is associated with elevated expression of α-DB at glial-vascular endfeet and (b) a deficiency in α-DB results in changes to the ECM and failure of IPAD. We used human post-mortem brain tissue with different severities of CAA and transgenic α-DB deficient mice. In human post-mortem tissue we observed a significant increase in vascular α-DB with CAA (CAA vrs. Old p < 0.005, CAA vrs. Young p < 0.005). In the mouse model of α-DB deficiency, there was early modifications to vascular ECM (collagen IV and BM thickening) that translated into reduced IPAD efficiency. Our findings highlight the important role of α-DB in maintaining structure and function of ECM, particularly as a pathway for the flow of ISF and solutes out of the brain by IPAD.


Subject(s)
Cerebral Amyloid Angiopathy/metabolism , Cerebral Amyloid Angiopathy/pathology , Dystrophin-Associated Proteins/metabolism , Extracellular Matrix/metabolism , Extracellular Matrix/pathology , Adult , Aged , Aged, 80 and over , Animals , Cerebrovascular Circulation/physiology , Humans , Male , Mice , Mice, Inbred C57BL , Middle Aged
3.
Front Pharmacol ; 12: 640179, 2021.
Article in English | MEDLINE | ID: mdl-34262448

ABSTRACT

Methicillin-resistant Staphylococcus aureus (MRSA) represents one of the most serious infectious disease concerns worldwide, with the CDC labeling it a "serious threat" in 2019. The current arsenal of antibiotics works by targeting bacterial growth and survival, which exerts great selective pressure for the development of resistance. The development of novel anti-infectives that inhibit quorum sensing and thus virulence in MRSA has been recurrently proposed as a promising therapeutic approach. In a follow-up of a study examining the MRSA quorum sensing inhibitory activity of extracts of Italian plants used in local traditional medicine, 224C-F2 was reported as a bioactive fraction of a Castanea sativa (European chestnut) leaf extract. The fraction demonstrated high activity in vitro and effective attenuation of MRSA pathogenicity in a mouse model of skin infection. Through further bioassay-guided fractionation using reverse-phase high performance liquid chromatography, a novel hydroperoxy cycloartane triterpenoid, castaneroxy A (1), was isolated. Its structure was established by nuclear magnetic resonance, mass spectrometry and X-ray diffraction analyses. Isomers of 1 were also detected in an adjacent fraction. In a series of assays assessing inhibition of markers of MRSA virulence, 1 exerted activities in the low micromolar range. It inhibited agr::P3 activation (IC50 = 31.72 µM), δ-toxin production (IC50 = 31.72 µM in NRS385), supernatant cytotoxicity to HaCaT human keratinocytes (IC50 = 7.93 µM in NRS385), and rabbit erythrocyte hemolytic activity (IC50 = 7.93 µM in LAC). Compound 1 did not inhibit biofilm production, and at high concentrations it exerted cytotoxicity against human keratinocytes greater than that of 224C-F2. Finally, 1 reduced dermonecrosis in a murine model of MRSA infection. The results establish 1 as a promising antivirulence candidate for development against MRSA.

4.
Gut Microbes ; 13(1): 1-6, 2021.
Article in English | MEDLINE | ID: mdl-33966605

ABSTRACT

Varieties and cultivars of the cruciferous vegetable Brassica oleracea are widely presumed to elicit positive influences on mammalian health and disease, particularly related to their indole and sulforaphane content. However, there is a considerable gap in knowledge regarding the mechanisms whereby these plant-derived molecules elicit their beneficial effects on the host. In this study, we examined the chemical variation between B. oleracea varieties and evaluated their capacity to both activate Nrf2 in the Drosophila intestine and elicit cytoprotection. Ten types of edible B. oleracea were purchased and B. macrocarpa was wild collected. Fresh material was dried, extracted by double maceration and green kale was also subjected to anaerobic fermentation before processing. Untargeted metabolomics was used to perform Principal Component Analysis. Targeted mass spectral analysis determined the presence of six indole species and quantified indole. Extracts were tested for their capacity to activate Nrf2 in the Drosophila intestine in third instar Drosophila larvae. Cytoprotective effects were evaluated using a paraquat-induced oxidative stress gut injury model. A "Smurf" assay was used to determine protective capacity against a chemically induced leaky gut. Extracts of Brussels sprouts and broccoli activated Nrf2 and protected against paraquat-induced damage and leaky gut. Lacto-fermented kale showed a cytoprotective effect, increasing survival by 20% over the non-fermented extract, but did not protect against leaky gut. The protective effects observed do not directly correlate with indole content, suggesting involvement of multiple compounds and a synergistic mechanism.


Subject(s)
Brassica/chemistry , Drosophila/drug effects , Plant Extracts/pharmacology , Protective Agents/pharmacology , Animals , Drosophila/genetics , Drosophila/growth & development , Drosophila/metabolism , Drosophila Proteins/genetics , Drosophila Proteins/metabolism , Intestines/drug effects , Larva/drug effects , Larva/genetics , Larva/growth & development , Larva/metabolism , NF-E2-Related Factor 2/genetics , NF-E2-Related Factor 2/metabolism , Oxidative Stress/drug effects , Plant Extracts/chemistry , Protective Agents/chemistry , Vegetables/chemistry
5.
Chem Rev ; 121(6): 3495-3560, 2021 03 24.
Article in English | MEDLINE | ID: mdl-33164487

ABSTRACT

The crisis of antibiotic resistance necessitates creative and innovative approaches, from chemical identification and analysis to the assessment of bioactivity. Plant natural products (NPs) represent a promising source of antibacterial lead compounds that could help fill the drug discovery pipeline in response to the growing antibiotic resistance crisis. The major strength of plant NPs lies in their rich and unique chemodiversity, their worldwide distribution and ease of access, their various antibacterial modes of action, and the proven clinical effectiveness of plant extracts from which they are isolated. While many studies have tried to summarize NPs with antibacterial activities, a comprehensive review with rigorous selection criteria has never been performed. In this work, the literature from 2012 to 2019 was systematically reviewed to highlight plant-derived compounds with antibacterial activity by focusing on their growth inhibitory activity. A total of 459 compounds are included in this Review, of which 50.8% are phenolic derivatives, 26.6% are terpenoids, 5.7% are alkaloids, and 17% are classified as other metabolites. A selection of 183 compounds is further discussed regarding their antibacterial activity, biosynthesis, structure-activity relationship, mechanism of action, and potential as antibiotics. Emerging trends in the field of antibacterial drug discovery from plants are also discussed. This Review brings to the forefront key findings on the antibacterial potential of plant NPs for consideration in future antibiotic discovery and development efforts.


Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Infective Agents/chemistry , Biological Products/chemistry , Plant Extracts/chemistry , Plants/chemistry , Alkaloids/chemistry , Alkaloids/pharmacology , Animals , Anti-Bacterial Agents/pharmacology , Anti-Infective Agents/pharmacology , Biological Products/pharmacology , Drug Discovery , Drug Resistance, Microbial , Humans , Phenols/chemistry , Phenols/pharmacology , Plant Extracts/pharmacology , Structure-Activity Relationship , Terpenes/chemistry , Terpenes/pharmacology
6.
Sci Rep ; 10(1): 11935, 2020 07 20.
Article in English | MEDLINE | ID: mdl-32686689

ABSTRACT

Antibiotic resistance poses one of the greatest threats to global health today; conventional drug therapies are becoming increasingly inefficacious and limited. We identified 16 medicinal plant species used by traditional healers for the treatment of infectious and inflammatory diseases in the Greater Mpigi region of Uganda. Extracts were evaluated for their ability to inhibit growth of clinical isolates of multidrug-resistant ESKAPE pathogens. Extracts were also screened for quorum quenching activity against S. aureus, including direct protein output assessment (δ-toxin), and cytotoxicity against human keratinocytes (HaCaT). Putative matches of compounds were elucidated via LC-FTMS for the best-performing extracts. These were extracts of Zanthoxylum chalybeum (Staphylococcus aureus: MIC: 16 µg/mL; Enterococcus faecium: MIC: 32 µg/mL) and Harungana madagascariensis (S. aureus: MIC: 32 µg/mL; E. faecium: MIC: 32 µg/mL) stem bark. Extracts of Solanum aculeastrum root bark and Sesamum calycinum subsp. angustifolium leaves exhibited strong quorum sensing inhibition activity against all S. aureus accessory gene regulator (agr) alleles in absence of growth inhibition (IC50 values: 1-64 µg/mL). The study provided scientific evidence for the potential therapeutic efficacy of these medicinal plants in the Greater Mpigi region used for infections and wounds, with 13 out of 16 species tested being validated with in vitro studies.


Subject(s)
Anti-Infective Agents/pharmacology , Drug Resistance, Multiple, Bacterial/drug effects , Plant Extracts/pharmacology , Plants, Medicinal/chemistry , Anti-Infective Agents/chemistry , Bacterial Infections/drug therapy , Bacterial Infections/microbiology , Cell Survival/drug effects , Chromatography, Liquid , Dose-Response Relationship, Drug , Humans , Keratinocytes/drug effects , Keratinocytes/metabolism , Mass Spectrometry , Microbial Sensitivity Tests , Plant Extracts/chemistry , Quorum Sensing/drug effects , Staphylococcus aureus/drug effects , Uganda
7.
Sci Rep ; 10(1): 8046, 2020 05 15.
Article in English | MEDLINE | ID: mdl-32415287

ABSTRACT

Staphylococcus aureus relies on quorum sensing to exert virulence to establish and maintain infection. Prior research demonstrated the potent quorum sensing inhibition effects of "430D-F5", a refined extract derived from the fruits of Schinus terebinthifolia, a medicinal plant used for the traditional treatment of skin and soft tissue infections. We report the isolation and identification of three compounds from 430D-F5 that reduce virulence and abate dermonecrosis: 3-oxo-olean-12-en-28-oic acid (1), 3-oxotirucalla-7,24Z-dien-26-oic acid (2) and 3α-hydroxytirucalla-7,24 Z-dien-27-oic acid (3). Each compound inhibits all S. aureus accessory gene regulator (agr) alleles (IC50 2-70 µM). Dose-dependent responses were also observed in agr-regulated reporters for leucocidin A (lukA, IC50 0.4-25 µM) and glycerol ester hydrolase or lipase (gehB, IC50 1.5-25 µM). Surprisingly, dose-dependent activity against the nuclease reporter (nuc), which is under the control of the sae two-component system, was also observed (IC50 0.4-12.5 µM). Compounds 1-3 exhibited little to no effect on the agr-independent mgrA P2 reporter (a constitutive promoter from the mgrA two-component system) and the esxA reporter (under control of mgrA). Compounds 1-3 inhibited δ-toxin production in vitro and reduced dermonecrosis in a murine in vivo model. This is the first report of triterpenoid acids with potent anti-virulence effects against S. aureus.


Subject(s)
Anacardiaceae/chemistry , Anti-Bacterial Agents/pharmacology , Fruit/chemistry , Plant Extracts/pharmacology , Staphylococcus aureus/drug effects , Triterpenes/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/isolation & purification , Biofilms/drug effects , Dose-Response Relationship, Drug , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Plant Extracts/chemistry , Plant Extracts/isolation & purification , Staphylococcus aureus/pathogenicity , Triterpenes/chemistry , Triterpenes/isolation & purification , Virulence/drug effects
8.
PeerJ ; 8: e8717, 2020.
Article in English | MEDLINE | ID: mdl-32231873

ABSTRACT

BACKGROUND: The delta-toxin (δ-toxin) of Staphylococcus aureus is the only hemolysin shown to cause mast cell degranulation and is linked to atopic dermatitis, a chronic inflammatory skin disease. We sought to characterize variation in δ-toxin production across S. aureus strains and identify genetic loci potentially associated with differences between strains. METHODS: A set of 124 S. aureus strains was genome-sequenced and δ-toxin levels in stationary phase supernatants determined by high performance liquid chromatography (HPLC). SNPs and kmers were associated with differences in toxin production using four genome-wide association study (GWAS) methods. Transposon mutations in candidate genes were tested for their δ-toxin levels. We constructed XGBoost models to predict toxin production based on genetic loci discovered to be potentially associated with the phenotype. RESULTS: The S. aureus strain set encompassed 40 sequence types (STs) in 23 clonal complexes (CCs). δ-toxin production ranged from barely detectable levels to >90,000 units, with a median of >8,000 units. CC30 had significantly lower levels of toxin production than average while CC45 and CC121 were higher. MSSA (methicillin sensitive) strains had higher δ-toxin production than MRSA (methicillin resistant) strains. Through multiple GWAS approaches, 45 genes were found to be potentially associated with toxicity. Machine learning models using loci discovered through GWAS as features were able to predict δ-toxin production (as a high/low binary phenotype) with a precision of .875 and specificity of .990 but recall of .333. We discovered that mutants in the carA gene, encoding the small chain of carbamoyl phosphate synthase, completely abolished toxin production and toxicity in Caenorhabditis elegans. CONCLUSIONS: The amount of stationary phase production of the toxin is a strain-specific phenotype likely affected by a complex interaction of number of genes with different levels of effect. We discovered new candidate genes that potentially play a role in modulating production. We report for the first time that the product of the carA gene is necessary for δ-toxin production in USA300. This work lays a foundation for future work on understanding toxin regulation in S. aureus and prediction of phenotypes from genomic sequences.

9.
Front Pharmacol ; 11: 586548, 2020.
Article in English | MEDLINE | ID: mdl-33488385

ABSTRACT

Background: Antimicrobial resistance represents a serious threat to human health across the globe. The cost of bringing a new antibiotic from discovery to market is high and return on investment is low. Furthermore, the development of new antibiotics has slowed dramatically since the 1950s' golden age of discovery. Plants produce a variety of bioactive secondary metabolites that could be used to fuel the future discovery pipeline. While many studies have focused on specific aspects of plants and plant natural products with antibacterial properties, a comprehensive review of the antibacterial potential of plants has never before been attempted. Objectives: This systematic review aims to evaluate reports on plants with significant antibacterial activities. Methods: Following the PRISMA model, we searched three electronic databases: Web of Science, PubMed and SciFinder by using specific keywords: "plant," "antibacterial," "inhibitory concentration." Results: We identified a total of 6,083 articles published between 1946 and 2019 and then reviewed 66% of these (4,024) focusing on articles published between 2012 and 2019. A rigorous selection process was implemented using clear inclusion and exclusion criteria, yielding data on 958 plant species derived from 483 scientific articles. Antibacterial activity is found in 51 of 79 vascular plant orders throughout the phylogenetic tree. Most are reported within eudicots, with the bulk of species being asterids. Antibacterial activity is not prominent in monocotyledons. Phylogenetic distribution strongly supports the concept of chemical evolution across plant clades, especially in more derived eudicot families. The Lamiaceae, Fabaceae and Asteraceae were the most represented plant families, while Cinnamomum verum, Rosmarinus vulgaris and Thymus vulgaris were the most studied species. South Africa was the most represented site of plant collection. Crude extraction in methanol was the most represented type of extraction and leaves were the main plant tissue investigated. Finally, Staphylococcus aureus was the most targeted pathogenic bacteria in these studies. We closely examine 70 prominent medicinal plant species from the 15 families most studied in the literature. Conclusion: This review depicts the current state of knowledge regarding antibacterials from plants and provides powerful recommendations for future research directions.

10.
Anal Chem ; 92(2): 1687-1690, 2020 01 21.
Article in English | MEDLINE | ID: mdl-31860273

ABSTRACT

Preparative high-performance liquid chromatographic (prep-HPLC) systems are used in many research schemes including purifying products from reaction mixtures, fractionating natural product extracts, and isolating compounds. Manual fraction collection from a prep-HPLC is a common method; however, it often lacks the reproducibility of automated fraction collectors due to human error. Automated fraction collectors for prep-HPLC systems can add thousands of dollars to the cost of prep-HPLC and are thus not always available to budgetary constrained research programs. Nevertheless, an automated fraction collector is a tremendous resource for any lab that employs prep-HPLC methods. Using LEGO MINDSTORMS pieces and easily obtained lumber and a steel C-channel, we were able to deploy an automated fraction collector for only a fraction of the cost of a commercial instrument. The programming software allows for a simple interface to create fraction collection programs tailored to individual HPLC methods. This fraction collector can be connected to any LC system and tailored to collect fractions in nearly any size or shaped container. This fraction collector was designed to provide maximum versatility and will make automated fraction collection more accessible to all researchers. The simple interface allows for quickly adapting the fraction collector method to any liquid chromatographic separation, no matter how complex.


Subject(s)
Automation , Software , Chromatography, High Pressure Liquid/economics , Costs and Cost Analysis , Humans
11.
Front Pharmacol ; 10: 1206, 2019.
Article in English | MEDLINE | ID: mdl-31680977

ABSTRACT

Acne vulgaris is a common skin disease affecting adolescents and young adults of all ethnic groups, negatively impacting self-esteem, self-confidence, and social life. The Gram-positive bacteria Cutibacterium acnes colonizes the sebum-rich follicle and contributes to inflammation of the pilosebaceous gland. Long-term antibiotic therapies targeting C. acnes lead to the development of antimicrobial resistance, and novel acne vulgaris therapies are needed. This study investigated the C. acnes inhibitory activity of Callicarpa americana leaves, a native Southeastern United States shrub historically used by Native Americans to treat fever, stomachache, and pruritis. Flash chromatography fractions of the ethyl acetate-soluble C. americana ethanol leaf extract (649C-F9 and 649C-F13) exhibited MICs ranging from 16 to 32 µg ml-1 and IC50 range of 4-32 µg ml-1 against a panel of 10 distinct C. acnes isolates. Cytotoxicity against an immortalized human keratinocyte cell line (HaCaTs) skin was detected at more than eight times the dose required for growth inhibitory activity (IC50 of 256 µg ml-1 for 649C-F9 and IC50 of >512 µg ml-1 for 649C-F13). This work highlights the potential of C. americana leaf extracts as a cosmeceutical ingredient for the management of acne vulgaris. Further research is necessary to assess its mechanism of action and in vivo efficacy.

12.
Front Microbiol ; 10: 775, 2019.
Article in English | MEDLINE | ID: mdl-31057504

ABSTRACT

In the search for new therapeutic solutions to address an increasing number of multidrug-resistant bacterial pathogens, secondary metabolites from plants have proven to be a rich source of antimicrobial compounds. Ginkgo biloba, a tree native to China, has been spread around the world as an ornamental tree. Its seeds have been used as snacks and medical materials in Traditional Chinese Medicine (TCM), while over the last century its leaf extracts emerged as a source of rising pharmaceutical commerce related to brain health in Western medicine. Besides studies on the neuro-protective effects of Ginkgo, its antibacterial activities have gained more attention from researchers in the past decades, though its leaves were the main focus. We reviewed a 16th-century Chinese text, the Ben Cao Gang Mu by Li Shi-Zhen, to investigate the ancient prescription of Ginkgo seeds for skin infections. We performed antibacterial assays on various Ginkgo seed extracts against pathogens (Staphylococcus aureus, Cutibacterium acnes, Klebsiella pneumoniae, Acinetobacter baumannii, Streptococcus pyogenes) relevant to skin and soft tissue infections (SSTIs). We demonstrate here that Ginkgo seed coats and immature seeds exhibit antibacterial activity against Gram-positive skin pathogens (C. acnes, S. aureus, and S. pyogenes), and thus validated its use in TCM. We also identified one compound tied to the antibacterial activity observed, ginkgolic acid C15:1, and examine its toxicity to human keratinocytes. These results highlight the relevance of ancient medical texts as leads for the discovery of natural products with antimicrobial activities.

13.
Sci Rep ; 9(1): 7692, 2019 05 22.
Article in English | MEDLINE | ID: mdl-31118466

ABSTRACT

A shortage of conventional medicine during the American Civil War (1861-1865) spurred Confederate physicians to use preparations of native plants as medicines. In 1863, botanist Francis Porcher compiled a book of medicinal plants native to the southern United States, including plants used in Native American traditional medicine. In this study, we consulted Porcher's book and collected samples from three species that were indicated for the formulation of antiseptics: Liriodendron tulipifera, Aralia spinosa, and Quercus alba. Extracts of these species were tested for the ability to inhibit growth in three species of multidrug-resistant pathogenic bacteria associated with wound infections: Staphylococcus aureus, Klebsiella pneumoniae, and Acinetobacter baumannii. Extracts were also tested for biofilm and quorum sensing inhibition against S. aureus. Q. alba extracts inhibited growth in all three species of bacteria (IC50 64, 32, and 32 µg/mL, respectively), and inhibited biofilm formation (IC50 1 µg/mL) in S. aureus. L. tulipifera extracts inhibited biofilm formation (IC50 32 µg/mL) in S. aureus. A. spinosa extracts inhibited biofilm formation (IC50 2 µg/mL) and quorum sensing (IC50 8 µg/mL) in S. aureus. These results support that this selection of plants exhibited some antiseptic properties in the prevention and management of wound infections during the conflict.


Subject(s)
American Civil War , Anti-Infective Agents, Local/pharmacology , Aralia/chemistry , Biofilms/drug effects , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Herbal Medicine/history , Liriodendron/chemistry , Military Medicine/history , Plant Extracts/pharmacology , Plants, Medicinal/chemistry , Quercus/chemistry , Quorum Sensing/drug effects , Anti-Infective Agents, Local/isolation & purification , Anti-Infective Agents, Local/toxicity , Drug Resistance, Multiple, Bacterial , Gram-Positive Bacteria/physiology , History, 19th Century , Humans , Keratinocytes/drug effects , Molecular Structure , Phytotherapy , Plant Extracts/toxicity , Species Specificity , Wound Infection/drug therapy
14.
Front Pharmacol ; 10: 67, 2019.
Article in English | MEDLINE | ID: mdl-30792655

ABSTRACT

Plants in the genus Kalanchoe (Family: Crassulaceae) are used in traditional medicine throughout the tropics for treating a variety of conditions. Two species, Kalanchoe mortagei and K. fedtschenkoi, have established ethnobotanical usage but have been neglected in previous research concerning their potential bioactivity. Here, we provide a thorough review of the reported antimicrobial activities of Kalanchoe genus and evaluate the in vitro antibacterial effects of two previously unexplored species against a panel of multidrug-resistant bacteria, the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter cloacae). Plant specimens were collected and voucher specimens deposited in the Emory University Herbarium. Dried plant material was ground into a powder and extracted as ethanolic macerations or as aqueous decoctions. Extracts were tested against the ESKAPE pathogens for growth inhibitory activity. Cytotoxicity to human cells was assessed via a lactate dehydrogenase assay of treated human keratinocytes (HaCaTs). K. fedtschenkoi extracts demonstrated growth inhibitory effects against two Gram-negative species, A. baumannii (strain CDC-33) and P. aeruginosa (AH-71), as well as S. aureus (UAMS-1). In these cases, growth inhibition greater than 50% (IC50) was generally observed at concentrations of 256 µg mL-1, though one K. fedtschenkoi extract (1465, prepared from stems) exhibited an IC50 against A. baumannii at 128 µg mL-1. All extracts were well tolerated by HaCaTs (LD50 ≥ 256 µg mL-1). Chemical characterization using HPLC and chemical standards established the presence of caffeic acid and quercetin in both plant species, as well as kaempferol in K. fedtschenkoi. These results reveal K. fedtschenkoi to be a plant of medicinal interest, and future research should aim to characterize the bioactivity of this species and its active constituents through bioassay-guide fractionation. Effects on bacterial biofilm formation and quorum-sensing are also research topics of interest for this genus.

15.
Front Pharmacol ; 9: 815, 2018.
Article in English | MEDLINE | ID: mdl-30116190

ABSTRACT

Local people in the Sudhnoti district of Pakistan share a rich practice of traditional medicine for the treatment of a variety of ailments. We selected nine plants from the Sudhnoti ethnopharmacological tradition used for the treatment of infectious and inflammatory disease. Our aim was to evaluate the in vitro anti-infective potential of extracts from these species against multidrug-resistant (MDR) ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa, and Enterobacter species) pathogens. Plant specimens were collected in the Sudhnoti district of Pakistan and vouchers deposited in Pakistan and the USA. Dried bulk specimens were ground into a fine powder and extracted by aqueous decoction and maceration in ethanol. Extracts were assessed for growth inhibitory activity against ESKAPE pathogens and biofilm and quorum sensing activity was assessed in Staphylococcus aureus. Cytotoxicity to human cells was assessed via a lactate dehydrogenase assay of treated human keratinocytes (HaCaTs). Four ethanolic extracts (Zanthoxylum armatum, Adiantum capillus-venaris, Artemisia absinthium, and Martynia annua) inhibited the growth of MDR strains of ESKAPE pathogens (IC50: 256 µg mL-1). All extracts, with the exception of Pyrus pashia and M. annua, exhibited significant quorum quenching in a reporter strain for S. aureus agr I. The ethanolic extract of Z. armatum fruits (Extract 1290) inhibited quorum sensing (IC50 32-256 µg mL-1) in S. aureus reporter strains for agr I-III. The quorum quenching activity of extract 1290 was validated by detection of δ-toxin in the bacterial supernatant, with concentrations of 64-256 µg mL-1 sufficient to yield a significant drop in δ-toxin production. None of the extracts inhibited S. aureus biofilm formation at sub-inhibitory concentrations for growth. All extracts were well tolerated by human keratinocytes (LD50 ≥ 256 µg mL-1). Chemical analysis of extract 1290 by liquid chromatography-Fourier transform mass spectrometry (LC-FTMS) revealed the presence of 29 compounds, including eight with putative structural matches. In conclusion, five out of the nine selected anti-infective medicinal plants exhibited growth inhibitory activity against at least one MDR ESKAPE pathogen at concentrations not harmful to human keratinocytes. Furthermore, Z. armatum was identified as a source of quorum quenching natural products and further bioassay-guided fractionation of this species is merited.

16.
Front Microbiol ; 8: 1639, 2017.
Article in English | MEDLINE | ID: mdl-28943862

ABSTRACT

Hypericum perforatum L. (Hypericaceae), or St. John's Wort, is a well-known medicinal herb often associated with the treatment of anxiety and depression. Additionally, an oil macerate (Oleum Hyperici) of its flowering aerial parts is widely used in traditional medicine across the Balkans as a topical wound and ulcer salve. Other studies have shown that Oleum Hyperici reduces both wound size and healing time. Of its active constituents, the naphthodianthrone hypericin and phloroglucinol hyperforin are effective antibacterial compounds against various Gram-positive bacteria. However, hyperforin is unstable with light and heat, and thus should not be present in the light-aged oil macerate. Additionally, hypericin can cause phototoxic skin reactions if ingested or absorbed into the skin. Therefore, the established chemistry presents a paradox for this H. perforatum oil macerate: the hyperforin responsible for the antibacterial bioactivity should degrade in the sunlight as the traditional oil is prepared; alternately, if hypericin is present in established bioactive levels, then the oil macerate should cause photosensitivity, yet none is reported. In this research, various extracts of H. perforatum were compared to traditional oil macerates with regards to chemical composition and antibacterial activity (inhibition of growth, biofilm formation, and quorum sensing) vs. several strains of Staphylococcus aureus in order to better understand this traditional medicine. It was found that four Kosovar-crafted oil macerates were effective at inhibiting biofilm formation (MBIC50 active range of 0.004-0.016% v/v), exhibited moderate inhibition of quorum sensing (QSIC50 active range of 0.064-0.512% v/v), and contained detectable amounts of hyperforin, but not hypericin. Overall, levels of hypericin were much higher in the organic extracts, and these also exhibited more potent growth inhibitory activity. In conclusion, these data confirm that oil macerates employed in traditional treatments of skin infection lack the compound credited with phototoxic reactions in H. perforatum use and exhibit anti-biofilm and modest quorum quenching effects, rather than growth inhibitory properties against S. aureus.

17.
Front Microbiol ; 8: 496, 2017.
Article in English | MEDLINE | ID: mdl-28386254

ABSTRACT

Staphylococcus aureus is a leading cause of hospital-acquired infections. It is listed among the top "serious threats" to human health in the USA, due in large part to rising rates of resistance. Many S. aureus infections are recalcitrant to antibiotic therapy due to their ability to form a biofilm, which acts not only as a physical barrier to antibiotics and the immune system, but results in differences in metabolism that further restricts antibiotic efficacy. Development of a modular strategy to synthesize a library of phenolic glycosides allowed for bioactivity testing and identification of anti-biofilm compounds within an extract of the elmleaf blackberry (Rubus ulmifolius). Two ellagic acid (EA) derivatives, EA xyloside and EA rhamnoside, have been identified as components of the Rubus extract. In addition, EA rhamnoside has been identified as an inhibitor of biofilm formation, with activity comparable to the complex extract 220D-F2 (composed of a mixture of EA glycosides), and confirmed by confocal laser scanning microscopy analyses.

18.
J Diet Suppl ; 14(6): 640-652, 2017 Nov 02.
Article in English | MEDLINE | ID: mdl-28384001

ABSTRACT

Schisandra chinensis (Chinese starvine) is a popular dietary supplement with a rich history of use in traditional Chinese medicine. Schisandra glabra (bay starvine) is the only North American representative of the genus, and little is known about its history of traditional use, chemistry, and potential biological activity. In this study, we conducted comparative high-performance liquid chromatography-diode array detector (HPLC-DAD) analysis on S. glabra and S. chinensis fruits. Additional characterization of S. glabra was performed by liquid chromatography-Fourier transform mass spectrometry (LC-FTMS). Quantitative analysis of four bioactive marker compounds revealed that S. glabra does not have statistically higher levels of schisandrin A or schisandrol B than S. chinensis. S. glabra has lower levels of schisandrol A and γ-schisandrin. Total phenolic contents of the two species' fruits were not statistically different. S. glabra had higher total tannin content than S. chinensis. We discuss the relevance of this analytical analysis to the study of S. glabra as a potential dietary supplement ingredient and give specific consideration to the conservation challenges involved in commercially developing a regionally threatened species, even in semicultivated conditions.


Subject(s)
Dietary Supplements , Phytochemicals/analysis , Plant Extracts/analysis , Schisandra/chemistry , Chromatography, High Pressure Liquid , Cyclooctanes/analysis , Dioxoles/analysis , Fruit/chemistry , Lignans/analysis , Medicine, Chinese Traditional , Phenols/analysis , Polycyclic Compounds/analysis , Schisandra/classification , Spectroscopy, Fourier Transform Infrared , Tannins/analysis
19.
Sci Rep ; 7: 42275, 2017 02 10.
Article in English | MEDLINE | ID: mdl-28186134

ABSTRACT

Widespread antibiotic resistance is on the rise and current therapies are becoming increasingly limited in both scope and efficacy. Methicillin-resistant Staphylococcus aureus (MRSA) represents a major contributor to this trend. Quorum sensing controlled virulence factors include secreted toxins responsible for extensive damage to host tissues and evasion of the immune system response; they are major contributors to morbidity and mortality. Investigation of botanical folk medicines for wounds and infections led us to study Schinus terebinthifolia (Brazilian Peppertree) as a potential source of virulence inhibitors. Here, we report the inhibitory activity of a flavone rich extract "430D-F5" against all S. aureus accessory gene regulator (agr) alleles in the absence of growth inhibition. Evidence for this activity is supported by its agr-quenching activity (IC50 2-32 µg mL-1) in transcriptional reporters, direct protein outputs (α-hemolysin and δ-toxin), and an in vivo skin challenge model. Importantly, 430D-F5 was well tolerated by human keratinocytes in cell culture and mouse skin in vivo; it also demonstrated significant reduction in dermonecrosis following skin challenge with a virulent strain of MRSA. This study provides an explanation for the anti-infective activity of peppertree remedies and yields insight into the potential utility of non-biocide virulence inhibitors in treating skin infections.


Subject(s)
Anacardiaceae/chemistry , Quorum Sensing , Skin Diseases/pathology , Alleles , Animals , Anti-Bacterial Agents/pharmacology , Biofilms/drug effects , Disease Models, Animal , Hemolysin Proteins/pharmacology , Humans , Methicillin-Resistant Staphylococcus aureus/drug effects , Mice , Microbial Sensitivity Tests , Microbiota , Necrosis , Plant Extracts/chemistry , Plant Extracts/isolation & purification , Plant Extracts/toxicity , Quorum Sensing/drug effects , Skin/drug effects , Skin/microbiology , Skin/pathology , Skin Diseases/microbiology , Soft Tissue Infections/microbiology , Soft Tissue Infections/pathology , Toxins, Biological/chemistry , Toxins, Biological/toxicity , Virulence/drug effects
20.
Front Pharmacol ; 7: 425, 2016.
Article in English | MEDLINE | ID: mdl-27891094

ABSTRACT

Propionibacterium acnes is implicated in the pathogenesis of acne vulgaris, which impacts >85% of teenagers. Novel therapies are in high demand and an ethnopharmacological approach to discovering new plant sources of anti-acne therapeutics could contribute to filling this void in effective therapies. The aims of our study were two-fold: (1) To determine if species identified in ethnopharmacological field studies as having traditional uses for skin and soft tissue infection (SSTI) exhibit significantly more activity against P. acnes than species with no such reported use; and (2) Chemically characterize active extracts and assess their suitability for future investigation. Extracts of Italian medicinal (for acne and other skin infection) and randomly collected plants and fungi were screened for growth-inhibitory and anti-biofilm activity in P. acnes using broth microdilution methods. Bioactive extracts were chemically characterized by HPLC and examined for cytotoxicity against human keratinocytes (HaCaTs). Following evaluation of 157 extracts from 10 fungi and 58 plants, we identified crude extracts from seven species exhibiting growth inhibitory activity (MICs 64-256 µg mL-1). All active extracts were examined for cytotoxicity against HaCaTs; extracts from one fungal and one plant species were toxic (IC50 256 µg mL-1). HPLC analysis with chemical standards revealed many of these extracts contained chlorogenic acid, p-coumaric acid, ellagic acid, gallic acid, and tannic acid. In conclusion, species used in traditional medicine for the skin exhibited significantly greater (p < 0.05) growth inhibitory and biofilm eradication activity than random species, supporting the validity of an ethnobotanical approach to identifying new therapeutics. The anti-acne activity of three extracts is reported for the first time: Vitis vinifera leaves, Asphodelus microcarpus leaves, and Vicia sativa aerial parts.

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