Castaneroxy A From the Leaves of Castanea sativa Inhibits Virulence in Staphylococcus aureus.

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.

Ethnobotany of the Aegadian Islands: safeguarding biocultural refugia in the Mediterranean.

BACKGROUND: The Aegadian Islands are located west of Trapani, Sicily. Once the site of bountiful tuna fisheries and fruit orchards (plums, peaches, apricots), grapevines, prickly pears, and grains, the local economy is now based on tourism, and many traditional agricultural and maritime practices have been abandoned. In this study, we aimed to evaluate the state of traditional ecological knowledge (TEK) concerning the use of wild and cultivated plants and fungi for human health, food, maritime, and agricultural purposes on the islands of Levanzo, Favignana, and Marettimo and compare present-day practices with those documented in the past. METHODS: In-depth semi-structured interviews were conducted in Italian with 48 participants with prior informed consent from May 2016 to July 2017 and October 2018. Herbarium voucher specimens of wild species were collected for herbarium deposit. A rigorous literature review of scientific and other local reports on TEK of wild flora and their application in food, health, and household applications was undertaken for the purpose of comparing findings from this field study with prior reports. RESULTS: A total of 122 plant and five fungal taxa representing 54 families were cited for 355 uses. Among the most pervasive species in the landscape, Agave americana and A. sisalana had diverse applications in the past, which ranged from cordage for agricultural and maritime applications to tools for sewing, eating land snails, and constructing furniture. Fields of Ferula communis also dominate the landscape, and the dry stems were used extensively in furniture making; this species also serves as an environmental indicator for the location of the most preferred edible mushrooms, Pleurotus eryngii var. ferulae. Other important flora included topical medicinal applications of Glaucium flavum for hematomas and Artemisia arborescens for ritual bathing of newborns. CONCLUSION: While many plant-based traditions have disappeared from daily practice, especially those related to traditional fishing and health practices, they remain in the memories of the eldest subset of the population. Documenting this knowledge before it disappears from oral history is a key factor in reducing loss of TEK and biocultural diversity, safeguarding the role of the Aegadian Islands as biocultural refugia.

Ethnobotany and the Role of Plant Natural Products in Antibiotic Drug Discovery.

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.

A Systematic Review of Plants With Antibacterial Activities: A Taxonomic and Phylogenetic Perspective.

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.

Opportunities for plant natural products in infection control.

The continued spread of antimicrobial resistance represents one of the most serious infectious disease threats to global health. There is consensus that a key component of addressing this threat is to replenish the waning pipeline of antimicrobials, with attention being paid to novel mechanisms of action. This includes the development of new classes of classic bacteriostatic and bactericidal antibiotics as well as antivirulence drugs, and it is especially in these areas where plant natural products demonstrate great potential. To this end, we discuss the unique characteristics of plant natural products, the advantages of plants as a resource for anti-infective drug discovery, and recent technologies that have further enabled this path of inquiry. As a result of emerging realization of their advantages, plant natural products have recently enjoyed increased scrutiny in antimicrobial lead discovery, and they will continue to serve as a source of leads. We conclude that plant natural products represent a promising and largely untapped source of new chemical entities from which novel anti-infectives can be discovered.

Targeting Virulence in Staphylococcus aureus by Chemical Inhibition of the Accessory Gene Regulator System In Vivo.

Methicillin-resistant Staphylococcus aureus (MRSA) presents one of the most serious health concerns worldwide. The WHO labeled it as a "high-priority" pathogen in 2017, also citing the more recently emerged vancomycin-intermediate and -resistant strains. With the spread of antibiotic resistance due in large part to the selective pressure exerted by conventional antibiotics, the use of antivirulence strategies has been recurrently proposed as a promising therapeutic approach. In MRSA, virulence is chiefly controlled by quorum sensing (QS); inhibitors of QS are called quorum quenchers (QQ). In S. aureus, the majority of QS components are coded for by the accessory gene regulator (Agr) system. Although much work has been done to develop QQs against MRSA, only a few studies have progressed to in vivo models. Those studies include both prophylactic and curative models of infection as well as combination treatments with antibiotic. For most, high efficacy is seen at attenuating MRSA virulence and pathogenicity, with some studies showing effects such as synergy with antibiotics and antibiotic resensitization. This minireview aims to summarize and derive conclusions from the literature on the in vivo efficacy of QQ agents in MRSA infection models. In vitro data are also summarized to provide sufficient background on the hits discussed. On the whole, the reported in vivo effects of the reviewed QQs against MRSA represent positive progress at this early stage in drug development. Follow-up studies that thoroughly examine in vitro and in vivo activity are needed to propel the field forward and set the stage for lead optimization.