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.

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.

Porphyromonas gingivalis is the keystone pathogen of periodontitis, a chronic inflammatory disease which causes tooth loss and deterioration of gingiva. Medicinal plants have been traditionally used for oral hygiene and health and might play a role as antibacterial agents against oral pathogens. In this work, we aimed to evaluate the antibacterial activity of plants used for oral hygiene or symptoms of periodontitis against P. gingivalis. We first reviewed the literature to identify plant species used for oral hygiene or symptoms of periodontitis. Then, we cross-checked this species list with our in-house library of plant extracts to select extracts for testing. Antibacterial activity tests were then performed for each plant extract against P. gingivalis, and their cytotoxicity was assessed on HaCaT cells. The selectivity index (SI) was then calculated. A total of 416 plant species belonging to 110 families and 305 genera were documented through our literature search, and 158 plant species were noted as being used by North American Native peoples Once cross-checked with the extracts contained in our library of natural products, 30 matches were identified and 21 were defined as high priority. Of the 109 extracts from 21 plant species selected and tested, 21 extracts from 11 plants had higher than 90% inhibition on P. gingivalis at 64 μg/mL and were further selected for MIC (Minimum Inhibitory Concentration) assays. Out of 21 plant extracts, 13 extracts (7 plant species) had a SI > 10. Pistacia lentiscus fruits showed the best MIC with value of 8 μg/mL, followed by Zanthoxylum armatum fruits/seeds with a MIC of 16 μg/mL. P. lentiscus fruits also showed the highest SI of 256. Most of the extracts tested present promising antibacterial activity and low cytotoxicity. Further testing for biofilm eradication and examination of activity against other dental pathogens and oral commensals should be performed to confirm the potential of these extracts as antibacterial agents. Future work will focus on application of a bioassay-guided fractionation approach to isolating and identifying the most active natural products in the top performing extracts. This study can serve as a basis for their future development as ingredients for oral hygiene products.

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 (IC 50 64, 32, and 32 µg/mL, respectively), and inhibited biofilm formation (IC 50 1 µg/mL) in S. aureus . L. tulipifera extracts inhibited biofilm formation (IC 50 32 µg/mL) in S. aureus . A. spinosa extracts inhibited biofilm formation (IC 50 2 µg/mL) and quorum sensing (IC 50 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.

The rise of antibiotic resistance presents a significant healthcare challenge and precludes the use of many otherwise valuable antibiotics. One potential solution to this problem is the use of antibiotics in combination with resistance-modifying agents, compounds that act synergistically with existing antibiotics to resensitize previously resistant bacteria. In this study, 12­(S),16ξ-dihydroxycleroda-3,13-dien-15,16-olide, a clerodane diterpene isolated from the medicinal plant Callicarpa americana, was found to synergize with oxacillin against methicillin-resistant Staphylococcus aureus. This synergy was confirmed by checkerboard (fractional inhibitory concentration index (FICI) = 0.125) and time-kill assays, with a subinhibitory dose of 12­(S),16ξ-dihydroxycleroda-3,13-dien-15,16-olide causing the effective concentration of oxacillin to fall below the susceptibility breakpoint for S. aureus, a >32-fold decrease in both cases.

Mixtures of drugs often have greater therapeutic value than any of their constituent drugs alone, and such combination therapies are widely used to treat diseases such as cancer, malaria, and viral infections. However, developing useful drug mixtures is challenging due to complex interactions between drugs. Natural substances can be fruitful sources of useful drug mixtures because secondary metabolites produced by living organisms do not often act in isolation in vivo. In order to facilitate the study of interactions within natural substances, a new analytical method to quantify interactions using data generated in the process of bioassay-guided fractionation is presented here: the extract fractional inhibitory concentration index (EFICI). The EFICI method uses the framework of Loewe additivity to calculate fractional inhibitory concentration values by which interactions can be determined for any combination of fractions that make up a parent extract. The EFICI method was applied to data on the bioassay-guided fractionation of Lechea mucronata and Schinus terebinthifolia for growth inhibition of the pathogenic bacterium Acinetobacter baumannii. The L. mucronata extract contained synergistic interactions (EFICI = 0.4181) and the S. terebinthifolia extract was non-interactive overall (EFICI = 0.9129). Quantifying interactions in the bioassay-guided fractionation of natural substances does not require additional experiments and can be useful to guide the experimental process and to support the development of standardized extracts as botanical drugs.

The rise of antibiotic resistance has necessitated a search for new antimicrobials with potent activity against multidrug-resistant gram-negative pathogens, such as carbapenem-resistant Acinetobacter baumannii (CRAB). In this study, a library of botanical extracts generated from plants used to treat infections in traditional medicine was screened for growth inhibition of CRAB. A crude extract of Schinus terebinthifolia leaves exhibited 80% inhibition at 256 µg/mL and underwent bioassay-guided fractionation, leading to the isolation of pentagalloyl glucose (PGG), a bioactive gallotannin. PGG inhibited growth of both CRAB and susceptible A. baumannii (MIC 64–256 µg/mL), and also exhibited activity against Pseudomonas aeruginosa (MIC 16 µg/mL) and Staphylococcus aureus (MIC 64 µg/mL). A mammalian cytotoxicity assay with human keratinocytes (HaCaTs) yielded an IC50 for PGG of 256 µg/mL. Mechanistic experiments revealed iron chelation as a possible mode of action for PGG’s activity against CRAB. Passaging assays for resistance did not produce any resistant mutants over a period of 21 days. In conclusion, PGG exhibits antimicrobial activity against CRAB, but due to known pharmacological restrictions in delivery, translation as a therapeutic may be limited to topical applications such as wound rinses and dressings.

13Mixtures of drugs often have greater therapeutic value than any of their constituent drugs alone, 14 and such combination therapies are widely used to treat diseases such as cancer, malaria, and 15 viral infections. However, developing useful drug mixtures is challenging due to complex 16 interactions between drugs. Natural substances can be fruitful sources of useful drug mixtures 17 because secondary metabolites produced by living organisms do not often act in isolation in vivo. 18 In order to facilitate the study of interactions within natural substances, a new analytical method 19 to quantify interactions using data generated in the process of bioassay-guided fractionation is 20 presented here: the extract fractional inhibitory concentration index (EFICI). The EFICI method 21 uses the framework of Loewe additivity to calculate fractional inhibitory concentration values by 22 which interactions can be determined for any combination of fractions that make up a parent 23 extract. The EFICI method was applied to data on the bioassay-guided fractionation of Lechea 24 mucronata and Schinus terebinthifolia for growth inhibition of the pathogenic bacterium 25 Acinetobacter baumannii. The L. mucronata extract contained synergistic interactions (EFICI = 26 0.4181) and the S. terebinthifolia extract was non-interactive overall (EFICI = 0.9129). 27Quantifying interactions in the bioassay-guided fractionation of natural substances does not 28 require additional experiments and can be useful to guide the experimental process and to 29 support the development of standardized extracts as botanical drugs. 30 31 medicine is concerned (1). While single-compound drugs have revolutionized the treatment of 3 35 many conditions, the development of resistance, among other factors, has prompted a return to 36 combination therapies for several diseases, including cancer (2), malaria (3), HIV (4), and 37 antibiotic-resistant infections (5). Combination therapy has a variety of potential benefits, 38 including synergy: greater potency of a drug mixture than would be predicted from the activity 39 of each constituent drug. Drugs that interact synergistically in a mixture have the advantage of 40 requiring lower doses for efficacy compared to their isolated use (6), but even in the absence of 41 synergy, drug mixtures can exhibit lower toxicity and slow the development of resistance (7). 42 43 A major obstacle to the development of combination therapies is the complexity that exists by 44 definition in mixtures (8). Determining efficacy, toxicity, and pharmacokinetics is difficult 45 enough with a single compound, and each additional factor multiplies the study needed to vet a 46 medicine properly. Additionally, identifying which drugs to combine and in what ratio can be 47 arbitrary and very time-consuming, particularly when investigating mixtures of more than two 48 drugs. Finally, there has been a struggle to develop and agree upon valid models, assays, and 49 analysis of the interactions present in drug mixtures (9, 1...