Antimicrobials from Plants

Our new review paper sheds light on recent advances in the discovery of antimicrobials from plants.

We have a new review paper from the Quave Lab published this week with the Royal Society of Chemistry journal Natural Product Reports!

Woo, S., L. Marquez, W.J. Crandall, C.J. Risener, C.L. Quave. (2023) Recent advances in the discovery of plant-derived antimicrobial natural products to combat antimicrobial resistant pathogens: insights from 2018–2022. Natural Product Reports. 40, 1271 - 1290. DOI: 10.1039/d2np00090c

The paper is available to folks with a subscription to the journal and here, I break down some of the main points.

What is AMR?

Antimicrobial resistance (AMR) is a significant public health threat that makes the treatment of infections increasingly challenging and, in some cases, impossible. It is a global issue that affects various bacterial species and geographic regions. The spread of AMR has been exacerbated during the COVID-19 pandemic, with a high percentage of hospitalized COVID-19 patients receiving antibiotics. To combat AMR, the development of rapid diagnostic methods and the discovery and development of new drug candidates are crucial.

Plant-derived natural products have played a vital role in the discovery and development of anti-infective drug candidates. They offer a diverse range of compounds with high structural complexity. Alkaloids, phenolic derivatives, and terpenoids from plants have shown promise as antibacterial lead compounds. Some plant-derived natural products not only target bacterial growth and survival but also exhibit synergistic effects with established antibiotics or target bacterial virulence and pathogenesis pathways.

Bacterial resistance to antimicrobials arises through mechanisms such as inactivation or alteration of antibacterial molecules, modification of bacterial target sites, and reduction of antibiotic penetration/accumulation. Plant natural products can act as antibacterial agents by targeting these resistance mechanisms and other pathways necessary for bacterial survival.

Scope and Methods of the Review

In this review, recent findings from the past five years (Jan 2018 – Sep 2022) on plant natural products with anti-infective properties against pathogenic bacteria are examined. The review also highlights the importance of ethnobotanical knowledge in the discovery of plant-derived natural products for treatment of infection.

The methods used for the review involved searching for relevant articles using specific keywords on PubMed and Google Scholar. The inclusion criteria focused on terrestrial plant-derived natural products with activity against multidrug-resistant bacteria. Only single compounds were included, excluding essential oils or extracts.

The review categorizes the reported natural products into three sections:

1. Antibacterial activity is assessed based on minimum inhibitory concentration (MIC), which indicates the lowest concentration of a compound that inhibits bacterial growth.

2. Antivirulence compounds target bacterial virulence factors without disrupting growth.

3. Antibiofilm compounds focus on inhibiting biofilm formation and damaging mature biofilms.

Chemical Classes Covered

Highlights for each chemical class covered in this review:

Alkaloids

• Alkaloids are diverse nitrogen-containing secondary metabolites produced by plants, microbes, and animals.

• Many plant alkaloids and their derivatives have medical applications such as pain relief, antimalarials, and treatment of hypotension.

Amide alkaloids

Amide alkaloids and derivatives with antimicrobial activity.

• Piperine (1) and piperlongumine (2) are amide alkaloids found in Piper species (pepper plants - black pepper, betle leaf, etc.).

• Piperine has multiple biological uses and has been found to have anti-tumor, antifungal, analgesic, and anti-depressant properties.

• Piperine and its derivatives show antibacterial activity against the pathogenic bacteria Staphylococcus aureus and Pseudomonas aeruginosa.

Phenolics

• Phenolics are the largest class of plant secondary metabolites, with over 8,000 known compounds.

• Phenolics play various roles in plants, including defense, signaling, pigment biosynthesis, and growth regulation.

• Phenolics with antibacterial properties include lignans, anthraquinones, coumarins, flavonoids, tannins, stilbenes, and methoxybenzenes.

Lignans

• Ligustchuanes A and B are lignan trimers with antibacterial activity against Staphylococcus aureus.

• Ligustchuanes disrupt the virulence of S. aureus through the disruption of α-Hemolysin.

Anthraquinones

Anthraquinones and derivatives with antimicrobial activity.

• Anthraquinones display a wide range of bioactivities, including anticancer, anti-arthritic, and laxative properties.

• Rhein, emodin (7), and other anthraquinones show antibiofilm activity against various bacteria strains.

Coumarins

• Umbelliferone and faselol are coumarins that inhibit biofilm formation in Staphylococcus epidermidis and Staphylococcus aureus.

• Umbelliferone also inhibits biofilm adherence in Staphylococcus epidermidis.

Flavonoids

• Flavonoids are a class of compounds with a C6-C3-C6 motif.

• Biochanin A, acacetin, and other flavonoids demonstrate antibacterial activity against Pseudomonas aeruginosa.

Tannins

• Corilagin is a hydrolysable tannin that inhibits hemolysis ability of Staphylococcus aureus and disrupts quorum sensing.

• Tannins have various biological activities, including anti-tumor and antioxidant properties.

Xanthones

• α-Mangostin, derived from Garcinia mangostana (mangosteen), inhibits biofilm attachment and formation in Staphylococcus aureus.

• Xanthones also exhibit anti-inflammatory and anti-viral activities.

Diarylheptanoids

• Curcumin is a diarylheptanoid with antibacterial activity against Streptococcus pneumoniae and Vibrio cholerae.

• Curcuminoids have been used in traditional medicine and are derived from Curcuma longa (turmeric).

Stilbenes

• Salvianolic acid A (24) inhibits the surface protein transpeptidase in Methicillin-resistant Staphylococcus aureus (MRSA).

• Resveratrol oligomers interfere with the type III secretion system (T3SS) of various pathogens.

Methoxybenzenes

• Paeonol inhibits the Salmonella enterica serovar Typhimurium type III secretion system (T3SS).

• Paeonol is derived from Paeonia suffruticosa (Moutan peony) and has various medicinal uses.

Terpenoids

Pentacyclic triterpenes with antibacterial activity.

• Terpenoids are a diverse class of compounds with various medicinal uses.

• Carnosic acid and andrographolide show antibacterial and antibiofilm activity.

• Pentacyclic triterpenoids and oleanolic acid derivatives exhibit antibacterial and antivirulence activity.

Overall, this review provides valuable information about plant-derived natural products that exhibit potential as antibiotics, antivirulence agents, and antibiofilm agents. It contributes to the natural product community by addressing the gap in comprehensive reviews on plant-derived natural products for anti-infective development.

Challenges and Next Steps

The chemical synthesis of derivatives from these natural compounds has demonstrated complementarity in medicinal chemistry for drug discovery. However, the research faces challenges, including the need for standardized reporting criteria, validation of plant materials, and consistent experimental protocols. Furthermore, the lack of preclinical animal studies for most compounds hinders their progress towards clinical trials and FDA approval.

The review highlights the urgent need for new antibiotics due to the global issue of antibiotic resistance (AMR) and the potential for an antibiotic crisis. Natural products have played a significant role in antimicrobial development, with plant-derived compounds showing promise in combating pathogenic bacteria. The review suggests exploring the use of nanoparticles for delivering natural products, as many compounds lack the necessary properties for optimal bioavailability and pharmacokinetics. Although few clinical trials have been conducted for the listed compounds, ongoing studies on their pharmacokinetic properties and safety profiles provide a promising first step.

The Takeaway

Traditional medicinal plants and ethnobotanical knowledge offer valuable starting points for the discovery and development of new drug candidates. Active collaboration between natural products researchers, microbiologists, medicinal chemists, and ethnobotanists is essential for the future development of effective anti-infective agents. Overall, plant-derived natural products hold great potential in filling the gap in medicine and inspiring the next generation of antimicrobials.

Yours in health, Dr. Quave

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Cassandra L. Quave, Ph.D. is a scientist, author, speaker, podcast host, wife, mother, explorer, and professor at Emory University School of Medicine. She teaches college courses and leads a group of research scientists studying medicinal plants to find new life-saving drugs from nature. She hosts the Foodie Pharmacology podcast and writes the Nature’s Pharmacy newsletter to share the science behind natural medicines. To support her effort, consider a paid or founding subscription, with founding members receiving an autographed 1st edition hardcover copy of her book, The Plant Hunter.