Mode of actions of some phytoconstituents of medicinal plants in controlling animal microbial disease

Introduction

Infectious microbial diseases in livestock are becoming a global health problem facing the veterinary sciences 1. The current trend worldwide is involvement of folklore medicine with primary health care systems 2. In this regard, medicinal plants have been and are still the major sources of medicine worldwide 3. Active phytoconstituents are increasingly being used as alternatives for synthetic chemicals in the treatment and development of live stocks due to their powerful properties and exceptional bioactivity 4. Ethnoveterinary medicine is based on traditional knowledge, skills, methods, and uses for treating diseases and keeping animals healthy. Ethnoveterinary medication is becoming more popular in underdeveloped nations because it is easy to find, prepare, and provide, and it is often free or very cheap 5. It could be very important for animal productivity as well as earning a living, and it often becomes the main technique for farmers to care for their animals 6. Dietary phytochemicals and medicinal plants are helpful and suitable substitutes to synthetic drugs according to their economic value, efficiency, non- resistance, renewability, and eco-friendly 7. They are naturally originated molecules possessing configurational diversity which impact, stress or stimulation to resident microbiota, thus, they could be a tool for prevention of many illnesses such as metabolic, inflammatory, infectious diseases and cancer 8. However, the antioxidant activity of the phytoconstituents prevents the loss in the livestock industry through stimulating animals’ fertility and protecting against diseases 1. Bioactive plant constituents that are included as feeding additives, possess a wide range of impacts on the animals, from health promotors and important for animal breeding to poisonous or even fatal 9. Bioactive plants and plant compounds like phenolics, flavonoids, alkaloids, saponins and terpenoids could be helpful and economically valuable, environmentally safe and possess valuable medicinal properties like reduction or prevention of the incidence of cancers, cardiovascular diseases, neurodegenerative diseases, acting as antimicrobial drugs and many other values 10. There is increasing interest in the livestock industry for reducing or eliminating feeding antibiotics as growth promotors due to the developing antibiotic-resistant microbes in order to find safer and effective alternatives of natural origin like the phytochemicals produces by medicinal plants 11. According to the FAO, lacking drugs for treating illnesses and infections leads to about 35% loss in the breeding industry in several developing countries due to bad animal health. There are two main causes for the legislative changes regarding using antibiotic growth promoters. One of them is trying to withstand against developing of microbial resistance while the other is the consumer demands for eliminating usage of non-plant xenobiotics from animal’s feed. Accordingly, phytomedicines could be helpful for managing diseases and mortality of animals especially in rural areas 12. Phytotherapy has been used for centuries, regardless the curative properties of the used plants were assured or not. Unluckily, there is little research about medicinal plants used in ethnoveterinary fields regarding their active constituents, mode of action, and applicability. Therefore, there is still a need for intensifying phytochemical, physiological, and phytopharmacological studies regarding these plant species 13. Zoonosis is an infectious disease which could be transferred between animals and humans. Around 61% pathogenic microbes are known to influence humans as zoonotic 14. where most of the dangerous infectious diseases are of zoonotic origin 15 and around 75% have originated from wild animals 16. The transmission of these pathogens occurs thorough close contact with infected animals, inhaling, ingesting, or contamination of mucous membranes and damaged skin 17. The sources of zoonotic pathogenic microbes in foodborne illnesses arise from rare cooked meat, seafood in addition to unpasteurized milk, dairies and vegetables 18. In veterinary medicine, both humans and animals have Staphylococcus aureus on their skin and mucous membranes. Additionally, it has been reported to cause mastitis in dairy animals and manifests in hens and farmed rabbits 19. Staphylococcus hyicus have been recognized to cause osteomyelitis to turkeys and exudative epidermitis to pigs 18. Staphylococci could be cured using antibiotics; however, emerging of methicillin-resistant Staphylococcus aureus (MRSA) 20 has enforced the search for drugs of natural origin to substitutes the antibiotics like phytochemicals.

In this regard, I will summarize several effects of some biologically active plants and their phytoconstituents on some animal health, with special attention to animal diseases.

The mode of action of medicinal plants and their active components:

A wide variety of secondary metabolites are produced by plants, including phenolics, flavonoids, tannins, terpenes, alkaloids, essential oils and polypeptides, which they act as protective substances against biotic and abiotic stressors. These metabolites are not only vital for plant survival but also have therapeutic importance for human and animals 21,22. The broad existence of such phytocompounds has illustrated their beneficial advantages as antioxidant, antibacterial, antiviral, and antifungal agents 23 and have exhibited the ability to overcome the increased antibiotic resistance in microbial pathogens 24.

Plants possess impressive impacts as stimulators of rumen fermentation and affecting microflora for increasing productivity and improving health 25. Azadirahta indica, Hobrrhena antidysentrica, Barberis aristata, Embelia ribes, Acorus calamus, Artemisia annua and Artemisia absinthium exhibited high anticoccidial potential as they are used for treatment of the infectious disease Coccidiosis that infect the digestive tract of poultry 26. Many plants secondary active constituents exhibited broad antimicrobial potential against many pathogenic intestinal bacteria 27. For instance, essential oils are used for controlling colonization and proliferation of Clostridium perfringens in the broilers gut 28 inhibiting Salmonella typhimurium and E.coli growth in pigs 9 or preventing infection with Bacillus anthracis in mice 29. Some phytochemicals like Trans-cinnamaldehyde in Cinnamomum verum, linolenic acid in Linum usitatissimum and extract of Terminalia chebula possess the ability to diminish E. coli levels in the mammary gland 30. Other components have anti-inflammatory effects like cynatratoside-C from Cynanchum atratum is capable of deactivating NF-κB complex, inhibiting TLR4 expression, and decreasing IL-1β, IL-6, and TNF-α production 31. The caffeic acid is capable of attenuating the production of proinflammatory cytokines through diminishing the p65 phosphorylation in the NF-κB route and the IκBα degradation 32. Persicaria pensylvanica crude extracts exhibit bactericidal activity against S. aureus that causes contagious mastitis in dairy cows with economic withdraw of about two billion dollars per year in the United States and mastitis elimination using antimicrobial therapy still difficult according to its capability of forming a biofilm, becoming a small colony variant, or gaining antimicrobial resistance. Antimicrobial phytochemical compounds of P. pensylvanica may act as substitutes to synthetic drugs for treatment of Staphylococcal infections in human and animals 33. Vitex mollis, Psidium guajava, Dalbergia retusa, and Crescential alata leaves extracts were found to act as potential antibiotics that possess antioxidant capabilities for inhibition of all the tested MRSA isolated from cattle’s and rabbits 34. Oregano extract was found to be efficient in treating E. coli O27, the most frequent serotype, which causes large losses in broiler farms 35. Among the phytoconstituents possesses antioxidant activity, antimicrobial activity and stimulates immune response are terpenoids including monoterpenes (fruits and spices), diterpenes (berries), triterpenes (olive oil), tetraterpenes (colored fruits and vegetables), sesquiterpenes (essential oils of plants), and phenolics including various subclasses like flavonoids (from tea and grapes) 36,37. These phytoconstituents with amphipathic or hydrophobic structure, could exhibit impact on the interaction with microbial membranes, regarding permeability and micro viscosity 38. The mode of action of these phytocompounds was interpreted on basis of their influence on binding-receptors, enzymes, ion-exchange channels, transporters, and biological pathways 39,40 as illustrated in Table 1

Table 1: Examples of useful phytochemicals and how they work against target strains of bacteria
ChemicalClass	Phytochemicals	Sources	Targeted pathogens	Mechanism of action	Reference
Alkaloids	Berberine	Berberi’s species	Escherichia coli	Cell division/Protein/DNA synthesis inhibition	43
Conessine	Holarrhena antidysenterica	Pseudomonas aeruginosa	Efflux pump inhibition (EPI)	44
Reserpine	Rauwolfia serpentina	Staphylococcus sp., Streptococcus sp.	(EPI)	45
Tomatidine	Solanaceous plants	Listeria, Bacillus andStaphylococcus spp.	ATP synthase inhibitor	46
Organosulfur	Allicin	Allium sativum	S. epidermidis,P. aeruginosa,	Sulfhydryl-dependent enzyme inhibitor, DNA/protein synthesis inhibitor	47
Ajoene	A. sativum	Campylobacter jejuni,Staphylococcus sp.,E. coli	Sulfhydryl-dependent enzyme inhibitor	48
Sulforaphane	Diplotaxis harra	E. coli	Membrane destruction, ATP synthase and DNA/protein synthesis inhibitor	49
Phenolics	Kaempferol	Alpinia calcarata	Methicillin-resistantS. aureus	(EPI)	50
Resveratrol	Vitis vinifera	C. jejuni	(EPI)	51
Taxifolin	A. cepa	Enterococcus faecalis	Beta-Ketoacyl acyl carrier protein synthase inhibitor	52
Coumarins	Aegelinol	Ferulago campestris	Enterobacter aerogenes, Salmonella enterica serovar Typhi, E. cloacae,S. aureus	DNA gyrase inhibitor (GR)	53
Osthole	Prangos hulusii	Bacillus subtilis, S. aureus,Klebsiella pneumoniae,	DNA (GR)	54
Terpenoids	Carvacrol	Thymus capitatus	E. coli, Enterobacter aerogenes, S. aureus, P. aeruginosa	Cell membrane disruption (CMD)	55
Cinnamaldehyde	Essential oils	E. coli and S. aureus	(CMD)	56
Eugenol	Essential oils	Methicillin-resistant S. aureus	(CMD)	57

Medicinal plants have antibacterial capabilities through several ways, such as destroying bacterial cell walls, reducing enzyme function, and altering immunological responses. For example, essential oil constituents like citral and linalool from plants such as Cymbopogon citratus and Lavandula angustifolia have been shown to damage the cytoplasmic and outer membranes of Gram-negative bacteria, leading to bacterial inactivation. Furthermore, compounds like berberine from Berberis vulgaris have been reported to hinder the action of β-lactamase enzymes, thereby enhancing the effectiveness of antibiotics against resistant bacterial strains41. Some of the commercially available plants and/or plant components that possess antimicrobial activities are listed in Table 2 42.

Table 2: List of some plants and their components that possess antimicrobial activity 42

Common name	Scientific name	phytochemicals	Biological Activity
Barberry	Berberis vulgaris	Berberine	Antibacterial, antiprotozoal
Black pepper	Piper nigrum	Piperine	Antifungal, antibacterial against Lactobacillus, Micrococcus, E. coli and E. faecalis
Cascara sagrada	Rhamnus purshiana	Tannins	Antibacterial, antifungal, and antiviral
Chamomile	Matricaria chamomilla	Anthemic acid	M. tuberculosis, S. typhimurium, S. aureus
Eucalyptus	Eucalyptus globulus	Tannin	Antibacterial and antiviral
Goldenseal	Hydrastis canadensis	Berberine, hydrastine	Antibacterial, active against Giardia duodenale, Trypanosomes
Licorice	Glycyrrhiza glabra	Glabrol	Antibacterial, active against S. aureus, M. tuberculosis
Onion	Allium cepa	Allicin	Antibacterial, antifungal (active against Candida spp.)
Grape	Mahonia aquifolia	Berberine	Active against Plasmodium, Trypanosomes
Thyme	Thymus vulgaris	Caffeic acid, Thymol, Tannins	Antibacterial, antifungal, and antiviral

The mode of action of phenolics and flavonoids as antimicrobials:

Phenolics are plant secondary metabolites having hydroxyl groups linked to aromatic rings and included in defense mechanisms against UV radiation or pathogenic infections58. They are broadly distributed in plants 59. These compounds play a crucial role as antimicrobial drugs against antibiotic-resistant pathogens by different mechanisms, for instance, there are plenty of phenolics in bilberry, cranberry, and blueberry, like anthocyanidins, flavone, luteolin, flavanols, myricetin, quercetin and epigallocatechin-3-gallate 59,60 ,in addition to others like galangin, puerarin, and ursolic acid are efficient as antimicrobial drugs 61. 3-p-Trans-coumaroyl-2hydroxyquinic acid expressed antioxidant and antimicrobial activities against S. aureus where it contains 2-hydroxyquinic acid moiety and p-coumaric acid, but the active moiety or group responsible for antibacterial activity is unclear 62. p-Coumaric acid expresses antibacterial potential against E. coli through destructing cell membranes and attaching its DNA genome leading to cells malfunctions 63. Flavonoids, including quercetin and kaempferol, are antioxidants that shield plants from oxidative stress due to environmental causes. They also play a role in signaling and defense against pathogens 64. Flavonoids, as a class of phenolics, possess the ability to kill or inhibit bacterial cells through different routes, including disruption of membranes and inhibition of nucleic acid synthesis (inhibition of dihydrofolate reductase, helicase, and gyrase/topoisomerase), as well as inhibition of bacterial virulence, for instance, toxins and quorum sensing, that destroy the formation of biofilms 65. They could also inhibit the cell envelope synthesis, which involves the inhibition of fatty acids and peptidoglycans synthesis (inhibiting Alanine–Alanine dipeptide synthesis, inhibiting the peptidoglycans cross-linking) 66. Flavonoids may also block efflux pumps, potentially reversing antimicrobial resistance 67. Moreover, inhibiting NADH-cytochrome c reductase in the respiratory chain so inhibiting ATP 66.

The mode of action of peptides as antimicrobials:

Antimicrobial polypeptides are small proteins made by various living organisms that help fight off harmful microbes and are important for health and food safety. They can act as natural alternatives to antibiotics and include types like, defensins, thionine, lactoferricin, lactoferrampin, lactoglobulins derived peptides, casein-derived peptides, and lysozyme-derived peptides 68–70. These peptides have different structures and are mostly positively charged, while plants produce unique defense proteins to protect against microbes, which are different from traditional antibiotics, as they are gene-coded 71,72. Antimicrobial peptides attach to negatively charged bacterial membranes, overcoming barriers like lipopolysaccharides in Gram-negative bacteria and acidic polysaccharides in Gram-positive bacteria, allowing them to disrupt membranes and reach the cytoplasmic layer 73. These peptides can also boost the immune response by activating immune cells and influencing how the body recognizes harmful microbes and their components 74. Antiviral peptides (AVPs) are crucial therapeutic agents because of rising virus resistance and the limited effectiveness of traditional medications 75. Antiviral peptides inhibit viruses at different stages of their cycle through a variety of ways 76. Certain AVPs can deactivate the virus by incorporating it into the viral envelope and cell membrane, which can destabilize the viral membrane or stop infection and likewise, they have the ability to attach to viral glycoproteins, which prevents the viruses from attaching to the surface of the host cell 77. However, some (like heparan for the herpes simplex virus) attach to host cell receptors, blocking the virus's ability to attach to its target receptor and deactivating it. Some, like influenza viruses, stop viral attachment and stop the virus cell's membranes from fusing^78,79. RNA and DNA can be AVPs' target sites80 ,moreover, as in the cases of the Junin virus (JV), HIV-1, and HSV-2, their objective is to damage the viral envelope, causing it to become unstable81. Modifying or disrupting cell signaling pathways, such as BMAP-18 (bovine myeloid antimicrobial peptide-18), which can deactivate the Zika virus (ZIKV) by interfering with interferon type 1 signaling, is another method of virus inhibition 82,83. A possible treatment for fungal infections may be antifungal peptides (AFPs). The majority of AFPs work by targeting particular targets and using membrane-associated mechanisms. Ergosterol is the primary membrane sterol in fungal membranes, along with PI concentration and sphingolipid composition. High selectivity and prevention of treatment resistance are made possible by definite targets such glucosylceramides, mannosyldiinositol phosphorylceramide, or a fungal protein target^84,85.

The mode of action of essential oils as antimicrobials:

Essential oils have garnered significant attention for their potent antimicrobial properties, offering a natural alternate to synthetic preservers and antibiotics. Their mode of action is multifaceted, targeting various cellular components and processes in microorganisms. Essential oils with compounds like terpenes can damage microbial membranes, increase their permeability and cause leakage of important cell materials, especially in E. coli under acidic conditions. Thymus capitatus oil can destroy cell walls in various bacteria, including MRSA, leading to loss of essential cell contents and increased effectiveness against resistant strains. These oils can also block the production of peptidoglycan, a key part of bacterial cell walls, which weakens the bacteria and can lead to their death, especially when combined with antibiotics like penicillin G 41,86.

These oils can also block DNA synthesis, crucial for bacteria to grow and multiply. For instance, Thymus capitatus essential oil was shown to prevent DNA replication in E. coli and MRSA, stopping their growth. Additionally, essential oils can hinder important enzymes needed for bacteria to survive. They can bind to these enzymes, disrupting their function, and making bacteria more vulnerable to antibiotics like β-lactam, as shown in studies with α-terpinyl acetate and citral 86. Essential oils can stop the growth of biofilms, which are tough groups of germs that resist treatments. They can break down the protective layer of biofilms, helping to fight infections, especially in hospitals, with Thymus pallescens oil being effective against certain bacteria at low amounts 87. These oils can also boost the effectiveness of regular antibiotics by working on different parts of the germs at once. When combined, they can make antibiotics work better against resistant germs, offering a possible way to tackle the issue of antibiotic resistance 88. Essential oils have antioxidant properties that help reduce stress in microbial cells, enhancing their ability to act as natural preservatives in food. Oils like rosemary, thyme, and tea tree are effective due to their strong antioxidant activity 89. These oils can also fight airborne germs by releasing volatile compounds that disrupt microbial cell membranes, showing effectiveness against harmful bacteria like E. coli and Pseudomonas aeruginosa when used in gaseous form 90. Essential oils can fight many germs like bacteria and fungi, making it hard for them to resist. Garlic and rose oils are especially effective against spoilage microbes, with specific amounts needed to stop their growth 89,91. Using nanomaterials and mixing essential oils with other substances can boost their effectiveness. For example, combining thyme and rose oils improves their antioxidant and antimicrobial benefits 88,89,91.

The essentials oils from medicinal plants like basil, citrus, lemon grass, oregano, rosemary and thyme expressed antifungal potential against large number of pathogenic fungi 92. Garlic and clove expressed the potential of inhibiting Candida acutus, C. albicans, C. apicola, C. catenulata, Rhodotorula rubra and Trignopsis variabilis 93. Isothiocyanate isolated from onion and garlic plants have the ability to deactivate the extracellular enzymes by breaking of di-sulphide bond 94. Oregano and thyme essential oils are capable of inhibiting fungal pathogens according to the presence of the phenolics like carvacrol and thymol that might disrupt fungal cell membranes 95. Clove and cinnamon are efficient against Aspergillus parasiticus and Fusarium moniliforme 96. Essential oils have the ability to penetrate and damage the fungal cell wall, cytoplasmic and mitochondrial membranes by changing the electron transport chain in mitochondria and destroying lipids, proteins, and nucleic acids within the cell 97. The essential oils could be able to decrease the membrane potential, affecting Ca+2 ions channels, decreasing the pH and influencing the proton pump and ATP levels. The changes of membranes fluidity led to leaking of radicals, cytochrome C, Ca+2 ions and proteins resulting in cell death by apoptosis and necrosis 98,99.

Recently, plant extracts and their biological activity have gained the interest of researchers as phytoconstituents possess antiviral potential through various modes of action. They could attach to certain sites on virion surface and prevent target cell recognition by virus 100,101. Different modes of action were identified where such phytoconstituents capable of blocking targets on the host cell surface, the penetration into the cell and the synthesis of viral nucleic acids. They might also be capable of inhibiting viral proteins synthesis and post translational processing. Another action is assembling daughter virions, or releasing the viral daughter particles from host cell 102. Melissa officinalis contains the essential oils citral and citronellal that are capable of inhibiting Herpes simplex virus type 2 (HSV-2) 103. Herpes simplex virus type 1 (HSV-1) replication can be inhibited by the in-vitro incubation of various essential oils. essential oils extracted from Artemisia arborescens could strongly suppress the (HSV-1), that causes common viral infections in humans. Essential oils have been used as antivirals in animals 104 and could be used as alternatives to the synthesized antiviral drugs 105,106.

The mode of action of alkaloids as antimicrobials:

Alkaloids have antibacterial activity against bacteria, fungus, and other pathogens, making them ideal candidates for the creation of natural antimicrobial drugs 107,108. Their mode of action could be through DNA intercalation, targeting RNA polymerase, gyrase, topoisomerase, the inhibition of cell division 109. Another investigation found that its antibacterial activities are associated with the inhibiting of the cell division protein FtsZ 43. Ungermane is an iso-quinoline alkaloid found in the methanolic extract of Pancratium illyricum L., that possess antibacterial potential. It could increase DNA cleavage through attacking and inhibiting the bacterial topoisomerase IA 110. Alkaloids can boost the immune system by activating stress resistance pathways and lowering harmful substances in the body, helping to fight infections like MRSA. They show potential for use in treatments 111. These compounds can also disrupt how bacteria move and form protective layers, making it harder for them to infect the host. Specific alkaloids, like piperine, can improve the effectiveness of antibiotics by helping them penetrate bacterial layers, making them useful in treating infections related to biofilms 112. Alkaloids can block bacterial efflux pumps, which helps keep antibiotics inside the bacteria, making them more effective against drug-resistant strains like E. coli. This can lower the amount of antibiotics needed to fight infections 113. Some alkaloids also target harmful factors in bacteria and help the immune system, reducing inflammation and aiding in healing. For example, 6-ethoxysanguinarine can lessen the effects of toxins in MRSA and help wounds heal faster. These properties of alkaloids make them promising options for treating tough infections, as they can both fight bacteria and support the body's healing processes 114. The chemical structure of alkaloids affects their ability to fight bacteria, with changes like methylation improving their strength and effectiveness. Isoquinoline alkaloids show better activity than their simpler forms, and modifications can enhance their interaction with bacterial membranes 115. Alkaloids can work together with traditional antibiotics to make them more effective against resistant bacteria. They help antibiotics penetrate biofilms and make bacteria more vulnerable, as seen with piperine improving the action of ciprofloxacin and azithromycin 112. Using alkaloids alongside antibiotics could be a smart way to tackle drug-resistant infections, potentially reducing the need for higher doses or longer treatments. This approach highlights the importance of understanding how alkaloids can enhance antibiotic therapy 113. Alkaloids are safe for use in medicine due to their low toxicity to human cells and their ability to target harmful microbes specifically, making them good candidates for new antimicrobial drugs 116. They work effectively against bacteria by disrupting their cell membranes, blocking harmful processes, and reducing their ability to cause disease, which is important for fighting drug-resistant bacteria. Compounds like oroidin and 6-ethoxysanguinarine show strong antibacterial effects while being safe for human cells, highlighting their potential in developing effective treatments with fewer side effects 114.

The mode of action of tannins compounds as antimicrobials:

Tannins are water-soluble phenolics abundantly dispersed in plants with the capacity to precipitate proteins 117. Tannins could be divided to condensed and hydrolysable 118. Hydrolysable tannins are numerous esters with d-glucose, whereas condensed tannins, such as proanthocyanidins, have building units of flavonoid monomers. There is increasing interest in using tannins for enhancing nutrition and animal health, especially for ruminants like cattle 119. Tannins are capable of reducing the risk of livestock illnesses and transmission of zoonotic pathogenic microbes 120. Tannic acid is a natural phytoconstituent possessing unique antimicrobial properties as antiviral and antibacterial effect. Activity against viruses like Influenzas A, Papilloma, noroviruses, and human immunodeficiency virus. It expressed broad antibacterial spectrum for instance, S. aureus, E. coli, S. pyogenes, E. faecalis, P. aeruginosa, Yersinia enterocolitica, L. innocua 121. Tannic acid express activity against viruses through inhibiting receptors binding, stopping viruses’ attachment to the various types of surfaces and inhibiting proteins attachment to cells that are important for the metabolism 122. Tannic acid could inhibit the bacterial attachment 123. The absence of bacterial cohesion to the surface leads to bacterial cell death. Also, tannic acid inhibits sugar and amino acid usage by bacteria for limiting bacterial growth 124. The antibacterial mechanism of action of tannins is attributed to their ability for passing the bacterial cell wall and interfering the cell metabolism leading to destruction. Tannins demonstrated fast activity in Gram-positive bacteria, but slow activity in Gram-negative bacteria, which are more toxic and cause specific diseases, due to the presence of a bilayer membrane. Tannic acid has been tested against several species of bacteria including S. aureus and E. coli 122.

The mode of action of saponins compounds as antimicrobials:

Saponins are a group of plant active phytoconstituents. They include glycosylated steroids, triterpenoids, and steroid alkaloids. Such saponins possess the capability of modifying rumen fermentation and enhancing animal production 125. They found to be present in the plants Yucca schidigera, Quillaja saponaria, Acacia auriculiformins, Sapindus saponaria, Sesbania sesban and Medicago sativa 126. Saponins are used in folkloric treatments to treat animal diseases. They are a category of high molecular-weight glycosides that may react with a triterpene to produce triterpene saponins or with a steroid to form steroid saponins 127. They could be monodesmosidic like Spirostanol, bidesmosidic like furostanol or tridesmosidic like lucerne 128. Saponins present in seeds, roots and bulbs of different plants 117. Saponins' ability to combat microorganisms depends on how they interact with their sterol moiety 127. Saponins has strong antifungal and antibacterial properties against infections such as Candida, Trichophyton species and methicillin-resistant Staphylococcus aureus and other multidrug-resistant pathogens. Additionally, because saponins can alter host immune responses and disrupt lipid membranes, they demonstrate potential in defending against viral diseases 129.

The mode of action of organosulfur compounds as antimicrobials:

Sulfur-containing substances like allicin, ajoene, dialkenyl, dialkyl sulphides, S-allylcysteine, and isothiocyanates have a broad antibacterial broad spectrum 23. Allicin (diallyl thiosulfinate) present in garlic (Allium sativum), a species in the family Alliaceae that exhibited antibacterial activity against Staphylococcus epidermidis, P. aeruginosa, Streptococcus agalactiae and MRSA 47. The mode of allicin action as antimicrobial drug attributed to its ability to inhibit sulfhydryl-dependent enzymes like alcohol dehydrogenase, thioredoxin reductase, and RNA polymerase 130. The antibacterial activity of garlic organosulfur compounds possesses the ability to form disulfide bonds with the free sulfhydryl groups enzymes rendering them inactive leading to bacterial death. They could also interact with and disrupt the bacterial cell membrane leading to leakage of cell content and finally death. They are interfering with protein production, DNA replication and gene expression 131. Furthermore, allicin found to inhibit DNA and protein synthesis in addition to its ability to target RNA 132. Ajoene is another organosulfur compound present in garlic that possess broad-spectrum antimicrobial activities It is similar to allicin in antibacterial mechanism of action 48. Allyl isothiocyanates, is an organosulfur compound present in Armoracia rusticana and Eutrema japonicum and exhibits antibacterial activity against E. coli, S. pyogenes and S. aureus 133. Several modes of action were recorded where the vapors of this compound could damage cell wall integrity leading to leakage of cellular metabolites 134. It was proposed that these substances might cause the deactivation of important intracellular enzymes by oxidative destruction of disulfide bonds. It could also result in cell membranes pores leading to leakage of the intracellular components 132.

Conclusion:

Medicinal plants are considerably important regarding the needs for intensive and largescale production of animals and for preventing and controlling of their diseases. Locally available herbs contain a significant number of functional phytochemicals like flavonoids, polyphenols, alkaloids, saponins, polypeptides, tannins, anthraquinones and terpenes. The current review discusses these active phytoconstituents in the form of crude extracts or pure active compounds have which bioactivities like immunostimulatory, antimicrobial, antiviral, antiparasitic, appetizers and growth promotors. The review also discusses how each herbal plant had a unique, dose-dependent mechanism of action for a particular disease. Moreover, the toxicological safety research of medicinal plants needs to be more studied. The application technology of medicinal plants, including extraction, drug duration, and delivery routes, also requires more study. Understanding the mechanisms of medicinal plants action regarding animal diseases is very limited and further research needed to know these mechanisms. Last but not least, the usage of medicinal plants and their active phytoconstituents could be a safe, effective and suitable alternative to synthetic drugs and antibiotics.

Recommendations:

The global increase in antibiotic-resistant microbes resembles a great danger to successful treatment of microbial infections. There is a need for developing novel strategies aiding in combating antibiotic resistance. Phytochemicals that are distinguished by their various chemical configuration and modes of actions are crucial therapeutics for exploring bioactive phytoconstituents. However, continued research should be done for understanding the modes of action and also pharmacodynamic and pharmacokinetic properties of these constituents.

References:

1. Shin B, Park W. Zoonotic diseases and phytochemical medicines for microbial infections in veterinary science: current state and future perspective. Front Vet Sci. 2018;5:166.

2. Kessler CS, Perera PK, Puthiyedath R, Dhruva A. Editorial: The increasing relevance of traditional medicine systems for the primary health care sector and general practice: global research perspectives. Vol. 11, Frontiers in Medicine. Frontiers Media SA; 2024. p. 1533361.

3. Parvin S, Reza A, Das S, Miah MMU, Karim S. Potential Role and International Trade of Medicinal and Aromatic Plants in the World. Eur J Agric Food Sci. 2023;5:89–99.

4. Rezzoug M, Bakchiche B, Gherib A, Roberta A, Guido F, Kilinçarslan Ö, et al. Chemical composition and bioactivity of essential oils and Ethanolic extracts of Ocimum basilicum L. and Thymus algeriensis Boiss. & Reut. from the Algerian Saharan Atlas. BMC Complement Altern Med. 2019;19:1–10.

5. Njoroge GN, Bussmann RW. Herbal usage and informant consensus in ethnoveterinary management of cattle diseases among the Kikuyus (Central Kenya). J Ethnopharmacol. 2006;108:332–9.

6. Confessor MVA, Mendonça LET, Mourão JS, Alves RRN. Animals to heal animals: Ethnoveterinary practices in semiarid region, Northeastern Brazil. J Ethnobiol Ethnomed. 2009;5:1–9.

7. Karimi A, Majlesi M, Rafieian-Kopaei M. Herbal versus synthetic drugs; beliefs and facts. J nephropharmacology [Internet]. 2015;4:27–30. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28197471%0Ahttp://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC5297475

8. Salama MM, Ezzat SM, Salem MA. Bioactive lead compounds and molecular targets for the treatment of heart diseases. Phytochem as Lead Compd New Drug Discov. 2019;67–94.

9. Si W, Ni X, Gong J, Yu H, Tsao R, Han Y, et al. Antimicrobial activity of essential oils and structurally related synthetic food additives towards Clostridium perfringens. J Appl Microbiol. 2009;106:213–20.

10. Mahdi JG. Medicinal potential of willow: A chemical perspective of aspirin discovery. J Saudi Chem Soc. 2010;14:317–22.

11. Lillehoj H, Liu Y, Calsamiglia S, Fernandez-Miyakawa ME, Chi F, Cravens RL, et al. Phytochemicals as antibiotic alternatives to promote growth and enhance host health. Vet Res. 2018;49:1–18.

12. Kala CP, Dhyani PP, Sajwan BS. Developing the medicinal plants sector in northern India: Challenges and opportunities. J Ethnobiol Ethnomed. 2006;2:1–15.

13. Hussain K, Majeed MT, Ismail Z, Sadikun A, Ibrahim P. Traditional and complementary medicines: Quality assessment strategies and safe usage. South Med Rev [Internet]. 2009;2:19–23. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23093874%0Ahttp://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC3471167

14. Cunningham andrew A. A walk on the wild side—emerging wildlife diseases. Vol. 331, Bmj. British Medical Journal Publishing Group; 2005. p. 1214–5.

15. Taylor LH. latham SM, Woolhouse ME. Risk factors Hum Dis emergence Philos Trans R Soc L B Biol Sci. 2001;356:983–9.

16. Woolhouse MEJ, Haydon DT, Antia R. Epidemic thresholds and R0, the basic reproduction number. Trends Ecol Evol. 2005;5:238–44.

17. Shepheard MA, Fleming VM, Connor TR, Corander J, Feil EJ, Fraser C, et al. Historical Zoonoses and Other Changes in Host Tropism of Staphylococcus aureus, Identified by Phylogenetic Analysis of a Population Dataset. PLoS One. 2013;8:e62369.

18. Gremião IDF, Miranda LHM, Reis EG, Rodrigues AM, Pereira SA. Zoonotic Epidemic of Sporotrichosis: Cat to Human Transmission. PLoS Pathog. 2017;13:e1006077.

19. Cantas L, Suer K. Review: The important bacterial zoonoses in “One Health” concept. Front Public Heal. 2014;2:144.

20. Smith TC. Livestock-associated Staphylococcus aureus: the United States experience. PLoS Pathog. 2015;11:e1004564.

21. Moloney MG. Natural Products as a Source for Novel Antibiotics. Trends Pharmacol Sci. 2016;37:689–701.

22. Mazid M, Khan TA, Mohammad F. Role of secondary metabolites in defense mechanisms of plants. Biol Med. 2011;3:232–49.

23. Barbieri R, Coppo E, Marchese A, Daglia M, Sobarzo-Sánchez E, Nabavi SF, et al. Phytochemicals for human disease: An update on plant-derived compounds antibacterial activity. Microbiol Res. 2017;196:44–68.

24. Rossiter SE, Fletcher MH, Wuest WM. Natural Products as Platforms to Overcome Antibiotic Resistance. Chem Rev. 2017;117:12415–74.

25. Jiménez-Peralta FS, Salem AZM, Mejia-Hernández P, González-Ronquillo M, Albarrán-Portillo B, Rojo-Rubio R, et al. Influence of individual and mixed extracts of two tree species on in vitro gas production kinetics of a high concentrate diet fed to growing lambs. Livest Sci. 2011;136:192–200.

26. Kostadinović LM, Popović SJ, Puvača NM, Čabarkapa IS, Kormanjoš ŠM, Lević JD. Influence of Artemisia absinthium essential oil on antioxidative system of broilers experimentally infected with Eimeria oocysts. Vet Arh. 2016;86:253–64.

27. Provenza FD, Villalba JJ. The role of natural plant products in modulating the immune system: An adaptable approach for combating disease in grazing animals. Small Rumin Res. 2010;89:131–9.

28. Mitsch P, Zitterl-Eglseer K, Köhler B, Gabler C, Losa R, Zimpernik I. The effect of two different blends of essential oil components on the proliferation of Clostridium perfringens in the intestines of broiler chickens. Poult Sci. 2004;83:669–75.

29. Sasaki JI, Kita JI. Bacteriocidal activity of garlic powder against Bacillus anthracis. J Nutr Sci Vitaminol (Tokyo). 2003;49:297–9.

30. Kher MN, Sheth NR, Bhatt VD. In Vitro Antibacterial Evaluation of Terminalia chebula as an Alternative of Antibiotics against Bovine Subclinical Mastitis. Anim Biotechnol. 2019;30:151–8.

31. Hu G, Hong D, Zhang T, Duan H, Wei P, Guo X, et al. Cynatratoside-C from Cynanchum atratum displays anti-inflammatory effect via suppressing TLR4 mediated NF-κB and MAPK signaling pathways in LPS-induced mastitis in mice. Chem Biol Interact. 2018;279:187–95.

32. Liu M, Song S, Li H, Jiang X, Yin P, Wan C, et al. The protective effect of caffeic acid against inflammation injury of primary bovine mammary epithelial cells induced by lipopolysaccharide. J Dairy Sci. 2014;97:2856–65.

33. Abdi RD, Kerro Dego O. Antimicrobial activity of Persicaria pensylvanica extract against Staphylococcus aureus. Eur J Integr Med. 2019;29:100921.

34. Medina MFE, Alaba PA, Estrada-Zuñiga ME, Velázquez-Ordoñez V, Barbabosa-Pliego A, Salem MZM, et al. Anti-staphylococcal properties of four plant extracts against sensitive and multi-resistant bacterial strains isolated from cattle and rabbits. Microb Pathog. 2017;113:286–94.

35. Abu El Hammed W, Soufy H, EL-Shemy A, Nasr S, Dessouky M. Isolation and Molecular Identification of Avian Pathogenic Escherichia coli in Broiler Chickens Suffering from Colibacillosis in some Governorates in Egypt. Egypt J Vet Sci. 2022;53:31–41.

36. Newman DJ, Cragg GM. Natural Products, Derivatives and Mimics as Antitumour Agents. Spec Publ Soc Chem. 2010;320:3–36.

37. Russell W, Duthie G. Plant secondary metabolites and gut health: the case for phenolic acids. Proc Nutr Soc. 2011;70:389–96.

38. Edwards IA, Elliott AG, Kavanagh AM, Zuegg J, Blaskovich MAT, Cooper MA. Contribution of amphipathicity and hydrophobicity to the antimicrobial activity and cytotoxicity of β-hairpin peptides. ACS Infect Dis. 2016;2:442–50.

39. dos Santos ATB, Araújo TFS, da Silva LCN, Silva CB, Oliveira AFM, Araújo JM, et al. Organic extracts from Indigofera suffruticosa leaves have antimicrobial and synergic actions with erythromycin against Staphylococcus aureus. Front Microbiol. 2015;6:13.

40. González-Ortiz G, Quarles Van Ufford HC, Halkes SBA, Cerdà-Cuéllar M, Beukelman CJ, Pieters RJ, et al. New properties of wheat bran: Anti-biofilm activity and interference with bacteria quorum-sensing systems. Environ Microbiol. 2014;16:1346–53.

41. Noui Mehidi I, Ait Ouazzou A, Tachoua W, Hosni K. Investigating the Antimicrobial Properties of Essential Oil Constituents and Their Mode of Action. Molecules. 2024;29:4119.

42. Khameneh B, Iranshahy M, Soheili V, Fazly Bazzaz BS. Review on plant antimicrobials: A mechanistic viewpoint. Antimicrob Resist Infect Control. 2019;8:1–28.

43. Boberek JM, Stach J, Good L. Genetic evidence for inhibition of bacterial division protein FtsZ by berberine. PLoS One. 2010;5:e13745.

44. Siriyong T, Srimanote P, Chusri S, Yingyongnarongkul BE, Suaisom C, Tipmanee V, et al. Conessine as a novel inhibitor of multidrug efflux pump systems in Pseudomonas aeruginosa. BMC Complement Altern Med. 2017;17:1–7.

45. Sridevi D, Shankar C, Prakash P, Park JH, Thamaraiselvi K. Inhibitory effects of reserpine against efflux pump activity of antibiotic resistance bacteria. Chem Biol Lett. 2017;4:69–72.

46. Boulet ML, Isabelle C, Guay I, Brouillette E, Langlois JP, Jacques PÉ, et al. Tomatidine is a lead antibiotic molecule that targets staphylococcus aureus ATP Synthase subunit C. Antimicrob Agents Chemother. 2018;62:e02197-17.

47. Reiter J, Levina N, Van Der Linden M, Gruhlke M, Martin C, Slusarenko AJ. Diallylthiosulfinate (Allicin), a volatile antimicrobial from garlic (Allium sativum), kills human lung pathogenic bacteria, including MDR strains, as a vapor. Molecules. 2017;22:1711.

48. Rehman F, Mairaj S. Antimicrobial studies of allicin and ajoene. Int J Pharma Bio Sci. 2013;4:1095–105.

49. Wu HZ, Fei HJ, Zhao YL, Liu XJ, Huang YJ, Wu SW. Antibacterial mechanism of sulforaphane on escherichia coli. J Sichuan Univ (Medical Sci Ed. 2012;43:386–90.

50. Randhawa HK, Hundal KK, Ahirrao PN, Jachak SM, Nandanwar HS. Efflux pump inhibitory activity of flavonoids isolated from Alpinia calcarata against methicillin-resistant Staphylococcus aureus. Biol. 2016;71:484–93.

51. Klančnik A, Šikić Pogačar M, Trošt K, Tušek Žnidarič M, Mozetič Vodopivec B, Smole Možina S. Anti-Campylobacter activity of resveratrol and an extract from waste Pinot noir grape skins and seeds, and resistance of Camp. jejuni planktonic and biofilm cells, mediated via the CmeABC efflux pump. J Appl Microbiol. 2017;122:65–77.

52. Jeong KW, Lee JY, Kang D Il, Lee JU, Shin SY, Kim Y. Screening of flavonoids as candidate antibiotics against Enterococcus faecalis. J Nat Prod. 2009;72:719–24.

53. Basile A, Sorbo S, Spadaro V, Bruno M, Maggio A, Faraone N, et al. Antimicrobial and antioxidant activities of coumarins from the roots of Ferulago campestris (apiaceae). Molecules. 2009;14:939–52.

54. Tan N, Yazıcı-Tütüniş S, Bilgin M, Tan E, Miski M. Antibacterial activities of pyrenylated coumarins from the roots of Prangos hulusii. Molecules. 2017;22:1098.

55. Althunibat OY, Qaralleh H, Al-Dalin SYA, Abboud M, Khleifat K, Majali IS, et al. Effect of thymol and carvacrol, the major components of Thymus capitatus on the growth of Pseudomonas aeruginosa. J Pure Appl Microbiol. 2016;10:367–74.

56. Zhang Y Bin, Liu XY, Jiang PP, Li W Di, Wang YF. Mechanism and antibacterial activity of cinnamaldehyde against Escherichia coli and Staphylococcus aureus. Mod Food Sci Technol. 2015;31:31–5.

57. Ding Y, Ding C, Ye N, Liu Z, Wold EA, Chen H, et al. Discovery and development of natural product oridonin-inspired anticancer agents. Eur J Med Chem. 2016;122:102–17.

58. Lin D, Xiao M, Zhao J, Li Z, Xing B, Li X, et al. An overview of plant phenolic compounds and their importance in human nutrition and management of type 2 diabetes. Molecules. 2016;21:1374.

59. Da Silva CR, De Andrade Neto JB, De Sousa Campos R, Figueiredo NS, Sampaio LS, Magalhães HIF, et al. Synergistic effect of the flavonoid catechin, quercetin, or epigallocatechin gallate with fluconazole induces apoptosis in Candida tropicalis resistant to fluconazole. Antimicrob Agents Chemother. 2014;58:1468–78.

60. Miyazawa M, Yoshinaga S, Kashima Y, Nakahashi H, Hara N, Nakagawa H, et al. Chemical composition and characteristic odor compounds in essential oil from alismatis rhizoma (Tubers of alisma orientale). J Oleo Sci. 2016;65:91–7.

61. Chandar B, Poovitha S, Ilango K, MohanKumar R, Parani M. Inhibition of New Delhi metallo-β-lactamase 1 (NDM-1) producing Escherichia coli IR-6 by selected plant extracts and their synergistic actions with antibiotics. Front Microbiol. 2017;8:1580.

62. Wu Y, Bai J, Liu X, Liu L, Zhong K, Huang Y, et al. Antibacterial effect of 3-p-trans-coumaroyl-2-hydroxyquinic acid, a phenolic compound from needles of Cedrus deodara, on cellular functions of Staphylococcus aureus. RSC Adv. 2018;8:4969–75.

63. Alves MJ, Ferreira ICFR, Froufe HJC, Abreu RMV, Martins A, Pintado M. Antimicrobial activity of phenolic compounds identified in wild mushrooms, SAR analysis and docking studies. J Appl Microbiol. 2013;115:346–57.

64. Gupta A, Gupta KK, Gupta SK, Mishra PK. Transcriptional Regulation in Biosynthesis of Phytochemicals in Medicinal Plants Under Stress Conditions. In: Stress-responsive Factors and Molecular Farming in Medicinal Plants. Springer; 2023. p. 123–40.

65. Hooper DC, Jacoby GA. Topoisomerase inhibitors: Fluoroquinolone mechanisms of action and resistance. Cold Spring Harb Perspect Med. 2016;6:a025320.

66. Górniak I, Bartoszewski R, Króliczewski J. Comprehensive review of antimicrobial activities of plant flavonoids. Phytochem Rev. 2019;18:241–72.

67. Waditzer M, Bucar F. Flavonoids as inhibitors of bacterial efflux pumps. Molecules. 2021;26:6904.

68. Goyal RK, Mattoo AK. Plant antimicrobial peptides. Host Def Pept Their Potential as Ther Agents. 2016;59:111–36.

69. Clara Pestana-Calsa M, L. A. C. Ribeiro I, Calsa Jr. T. Bioinformatics-Coupled Molecular Approaches for Unravelling Potential Antimicrobial Peptides Coding Genes in Brazilian Native and Crop Plant Species. Curr Protein Pept Sci. 2010;11:199–209.

70. Jabbari S, Hasani R, Kafilzadeh F, Janfeshan S. Antimicrobial Peptides from Milk Proteins : A Prospectus. Ann Biol Res. 2012;3:5313–8.

71. de Oliveira SSS, Cherene MB, Taveira GB, de Oliveira Mello É, de Oliveira Carvalho A, Gomes VM. Plant Antimicrobial Peptides and Their Main Families and Roles: A Review of the Literature. Curr Issues Mol Biol. 2025;47:1.

72. Ma X, Wang Q, Ren K, Xu T, Zhang Z, Xu M, et al. A Review of Antimicrobial Peptides: Structure, Mechanism of Action, and Molecular Optimization Strategies. Fermentation. 2024;10:540.

73. Roque-Borda CA, Primo LMDG, Medina-Alarcón KP, Campos IC, Nascimento C de F, Saraiva MMS, et al. Antimicrobial Peptides: A Promising Alternative to Conventional Antimicrobials for Combating Polymicrobial Biofilms. Adv Sci. 2024;12:2410893.

74. Islam T, Tamanna NT, Sagor MS, Zaki RM, Rabbee MF, Lackner M. Antimicrobial Peptides: A Promising Solution to the Rising Threat of Antibiotic Resistance. Pharmaceutics. 2024;16:1542.

75. Di Somma A, Moretta A, Canè C, Cirillo A, Duilio A. Antimicrobial and antibiofilm peptides. Biomolecules. 2020;10:652.

76. Moravej H, Moravej Z, Yazdanparast M, Heiat M, Mirhosseini A, Moosazadeh Moghaddam M, et al. Antimicrobial Peptides: Features, Action, and Their Resistance Mechanisms in Bacteria. Microb Drug Resist. 2018;24:747–67.

77. Talapko J, Škrlec I. The principles, mechanisms, and benefits of unconventional agents in the treatment of biofilm infection. Pharmaceuticals. 2020;13:1–13.

78. Skalickova S, Heger Z, Krejcova L, Pekarik V, Bastl K, Janda J, et al. Perspective of use of antiviral peptides against influenza virus. Viruses. 2015;7:5428–42.

79. Ahmed A, Siman-Tov G, Hall G, Bhalla N, Narayanan A. Human antimicrobial peptides as therapeutics for viral infections. Viruses. 2019;11:704.

80. Mulder KCL, Lima LA, Miranda VJ, Dias SC, Franco OL. Current scenario of peptide-based drugs: the key roles of cationic antitumor and antiviral peptides. Front Microbiol. 2013;4:321.

81. Albiol Matanic VC, Castilla V. Antiviral activity of antimicrobial cationic peptides against Junin virus and herpes simplex virus. Int J Antimicrob Agents. 2004;23:382–9.

82. He M, Zhang H, Li Y, Wang G, Tang B, Zhao J, et al. Cathelicidin-derived antimicrobial peptides inhibit Zika virus through direct inactivation and interferon pathway. Front Immunol. 2018;9:722.

83. Li X, Zuo S, Wang B, Zhang K, Wang Y. Antimicrobial Mechanisms and Clinical Application Prospects of Antimicrobial Peptides. Molecules. 2022;27:2675.

84. di Luca M, Maccari G, Nifosí R. Treatment of microbial biofilms in the post-antibiotic era: Prophylactic and therapeutic use of antimicrobial peptides and their design by bioinformatics tools. Pathog Dis. 2014;70:257–70.

85. Rautenbach M, Troskie AM, Vosloo JA. Antifungal peptides: To be or not to be membrane active. Biochimie. 2016;130:132–45.

86. Aouadhi C, Jouini A, Maaroufi K, Maaroufi A. Antibacterial Effect of Eight Essential Oils against Bacteria Implicated in Bovine Mastitis and Characterization of Primary Action Mode of Thymus capitatus Essential Oil. Antibiotica. 2024;13:237.

87. Bouguenoun W, Benbelaid F, Mebarki S, Bouguenoun I, Boulmaiz S, Khadir A, et al. Selected antimicrobial essential oils to eradicate multi-drug resistant bacterial biofilms involved in human nosocomial infections. Biofouling. 2023;39:816–29.

88. Reddy S, Kaur K, Barathe P, Shriram V, Paul AT, Kumar V. Plant Essential Oils as Potent Antimicrobials. In: Medicinal Plants and Antimicrobial Therapies. Springer; 2024. p. 23–47.

89. Al-Refaie D, Mehyar GF, Shahein M. Functional Role of Essential Oils as Antimicrobial and Antioxidat Agents in Food Industry: A Review. Jordan J Agric Sci. 2023;19:70–88.

90. Ainseba N, Loukili N, Soulimane A, Bellifa S, Dib MEA, Muselli A. Antimicrobial and Antifungal Effects of Essential Oils from Origanum vulgare, Lavandula officinalis, and Syzygium aromaticum on Bacterial Strains through Gaseous Contact. Anti-Infective Agents. 2024;22:53–9.

91. Xia H, Liu D, Jin Y, Wang M, Qiao Z, Wu Q, et al. Antimicrobial activity of eight plant essential oils having antioxidant property against spoilage microbes. J Appl Microbiol. 2024;135:lxae196.

92. Kivanç M, Akgül A, Doǧan A. Inhibitory and stimulatory effects of cumin, oregano and their essential oils on growth and acid production of Lactobacillus plantarum and Leuconostoc mesenteroides. Int J Food Microbiol. 1991;13:81–5.

93. Ceylan E, Fung DYC. Antimicrobial activity of spices. J Rapid Methods Autom Microbiol. 2004;12:1–55.

94. Delaquis PJ, Mazza G. Antimicrobial properties of isothiocyanates in food preservation. Food Technol. 1995;49:73–84.

95. Ultee A, Smid EJ. Influence of carvacrol on growth and toxin production by Bacillus cereus. Int J Food Microbiol. 2001;64:373–8.

96. Juglal S, Govinden R, Odhav B. Spice oils for the control of co-occurring mycotoxin-producing fungi. J Food Prot. 2002;65:683–7.

97. Arnal-Schnebelen B, Hadji-Minaglou F, Peroteau JF, Ribeyre F, De Billerbeck VG. Essential oils in infectious gynaecological disease: A statistical study of 658 cases. Int J Aromather. 2004;14:192–7.

98. Maurya A, Prasad J, Das S, Dwivedy AK. Essential Oils and Their Application in Food Safety [Internet]. Vol. 5, Frontiers in Sustainable Food Systems. 2021. Available from: https://www.frontiersin.org/article/10.3389/fsufs.2021.653420

99. Yoon HS, Moon SC, Kim ND, Park BS, Jeong MH, Yoo YH. Genistein induces apoptosis of RPE-J cells by opening mitochondrial PTP. Biochem Biophys Res Commun. 2000;276:151–6.

100. Ni ZJ, Wang X, Shen Y, Thakur K, Han J, Zhang JG, et al. Recent updates on the chemistry, bioactivities, mode of action, and industrial applications of plant essential oils. Trends Food Sci Technol [Internet]. 2021;110:78–89. Available from: https://www.sciencedirect.com/science/article/pii/S0924224421000789

101. Sarowska J, Wojnicz D, Jama-Kmiecik A, Frej-Mądrzak M, Choroszy-Król I. Antiviral potential of plants against noroviruses. Molecules [Internet]. 2021;26. Available from: https://www.mdpi.com/1420-3049/26/15/4669

102. Perez G. RM. Antiviral activity of compounds isolated from plants. Pharm Biol. 2003;41:107–57.

103. Allahverdiyev A, Duran N, Ozguven M, Koltas S. Antiviral activity of the volatile oils of Melissa officinalis L. against Herpes simplex virus type-2. Phytomedicine. 2004;11:657–61.

104. Koch C, Reichling J, Schnitzler P. Essential oils inhibit replication of herpes simplex virus type 1 and type 2. Bot Med Clin Pract. 2017;192:192–7.

105. Baqui AAMA, Jabra-Rizk MA, DePaola LG, Falkler WA, Meiller TF. In vitro effect of oral antiseptics on human immunodeficiency virus-1 and herpes simplex virus type 1. J Clin Periodontol. 2001;28:610–6.

106. Primo V, Rovera M, Zanon S, Oliva M, Demo M, Daghero J, et al. Determination of the antibacterial and antiviral activity of the essential oil from Minthostachys verticillata (Griseb) Epling. Rev Argent Microbiol. 2001;33:113–7.

107. Gupta NS. Therapeutic Efficacy of the Plant Bioactive Phytochemicals with Special Reference to Alkaloids, Terpenoids, Phenolics and Cardiac Glycosides. Int J Plant Environ [Internet]. 2024;10:22–30. Available from: https://ijplantenviro.com/index.php/IJPE/article/view/1736

108. Yadav K, Divyadeepika, Joshi J. Biological activity of phytochemicals extracted from medicinal plants of Apocynaceae family. Mater Today Proc. 2024;

109. Domadia PN, Bhunia A, Sivaraman J, Swarup S, Dasgupta D. Berberine targets assembly of Escherichia coli cell division protein FtsZ. Biochemistry. 2008;47:3225–34.

110. Schrader KK, Avolio F, Andolfi A, Cimmino A, Evidente A. Ungeremine and its hemisynthesized analogues as bactericides against flavobacterium columnare. J Agric Food Chem. 2013;61:1179–83.

111. Qi J, Zhang X, Guo X, Yang Y, Fan X, Han Y, et al. Evaluation of the in vitro and in vivo antimicrobial activity of alkaloids prepared from Chelidonium majus L. using MRSA- infected C. elegans as a model host. Fitoterapia. 2024;175:105944.

112. Dusane DH, Hosseinidoust Z, Asadishad B, Tufenkji N. Alkaloids modulate motility, biofilm formation and antibiotic susceptibility of uropathogenic Escherichia coli. PLoS One. 2014;9:e112093.

113. Dwivedi GR, Gupta S, Maurya A, Tripathi S, Sharma A, Darokar MP, et al. Synergy potential of indole alkaloids and its derivative against drug-resistant Escherichia coli. Chem Biol Drug Des. 2015;86:1471–81.

114. Liu ZH, Wang WM, Zhang Z, Sun L, Wu SC. Natural Antibacterial and Antivirulence Alkaloids From Macleaya cordata Against Methicillin-Resistant Staphylococcus aureus. Front Pharmacol. 2022;13:813172.

115. Avci FG, Atas B, Gulsoy Toplan G, Gurer C, Sariyar Akbulut B. Antibacterial and antifungal activities of isoquinoline alkaloids of the Papaveraceae and Fumariaceae families and their implications in structure–activity relationships. Stud Nat Prod Chem. 2021;70:87–118.

116. Alghazeer R, Azwai S, Garbaj AM, Amr A, Elghmasi S, Sidati M, et al. Alkaloids rich extracts from brown algae against multidrug-resistant bacteria by distinctive mode of action. Arab J Sci Eng. 2022;1–10.

117. Evans SM, Cowan MM. Plant products as antimicrobial agents. Cosmet Drug Microbiol. 2016;12:205–31.

118. Redondo LM, Dominguez JE, Rabinovitz BC, Redondo EA, Fernández Miyakawa ME. Hydrolyzable and condensed tannins resistance in Clostridium perfringens. Anaerobe [Internet]. 2015;34:139–45. Available from: https://www.sciencedirect.com/science/article/pii/S1075996415300287

119. Frutos P, Hervás G, Giráldez FJ, Mantecón AR. Review. Tannins and ruminant nutrition. Spanish J Agric Res. 2004;2:191.

120. Tong Z, He W, Fan X, Guo A. Biological Function of Plant Tannin and Its Application in Animal Health. Front Vet Sci. 2022;8:1–7.

121. Kaczmarek B. Tannic acid with antiviral and antibacterial activity as a promising component of biomaterials-A minireview. Materials (Basel) [Internet]. 2020;13. Available from: https://www.mdpi.com/1996-1944/13/14/3224

122. Belhaoues S, Amri S, Bensouilah M. Major phenolic compounds, antioxidant and antibacterial activities of Anthemis praecox Link aerial parts. South African J Bot [Internet]. 2020;131:200–5. Available from: https://www.sciencedirect.com/science/article/pii/S0254629919322677

123. Vance SH, Tucci M, Benghuzzi H. Evaluation of the antimicrobial efficacy of green tea extract (EGCG) against streptococcus pyogenes in vitro. Biomed Sci Instrum [Internet]. 2011;47:177–82. Available from: http://europepmc.org/abstract/MED/21525617

124. Pandey A, Negi PS. Phytochemical composition, in vitro antioxidant activity and antibacterial mechanisms of Neolamarckia cadamba fruits extracts. Nat Prod Res [Internet]. 2018;32:1189–92. Available from: https://doi.org/10.1080/14786419.2017.1323209

125. Wina E, Muetzel S, Becker K. The impact of saponins or saponin-containing plant materials on ruminant production - A review. J Agric Food Chem [Internet]. 2005;53:8093–105. Available from: https://doi.org/10.1021/jf048053d

126. Patra AK, Saxena J. The effect and mode of action of saponins on the microbial populations and fermentation in the rumen and ruminant production. Nutr Res Rev. 2009;22:204–19.

127. Rosen JD. Saponins. K. Hostettmann and A. Marston. Analytical Biochemistry. Cambridge [etc: Cambridge Univ. Press; 1996. 119 p. (Chemistry and pharmacology of natural products; vol. 239).

128. Vincken JP, Heng L, de Groot A, Gruppen H. Saponins, classification and occurrence in the plant kingdom. Phytochemistry [Internet]. 2007;68:275–97. Available from: https://www.sciencedirect.com/science/article/pii/S0031942206006480

129. Ibrahim NA, Rathore D, Janiyani K, Gupta A, Sulieman AME, Tahir HE, et al. A comprehensive review on plant-derived bioactive saponins as promising antimicrobial agents: from bioavailability challenges, molecular mechanistic insights to therapeutic applications. Naunyn Schmiedebergs Arch Pharmacol. 2025;1–31.

130. Lanzotti V, Scala F, Bonanomi G. Compounds from Allium species with cytotoxic and antimicrobial activity. Phytochem Rev. 2014;13:769–91.

131. Bhatwalkar SB, Mondal R, Krishna SBN, Adam JK, Govender P, Anupam R. Antibacterial Properties of Organosulfur Compounds of Garlic (Allium sativum) [Internet]. Vol. 12, Frontiers in Microbiology. 2021. Available from: https://www.frontiersin.org/article/10.3389/fmicb.2021.613077

132. Khare T, Anand U, Dey A, Assaraf YG, Chen ZS, Liu Z, et al. Exploring Phytochemicals for Combating Antibiotic Resistance in Microbial Pathogens. Front Pharmacol. 2021;12.

133. Lu Z, Dockery CR, Crosby M, Chavarria K, Patterson B, Giedd M. Antibacterial activities of wasabi against Escherichia coli O157: H7 and Staphylococcus aureus. Front Microbiol. 2016;7:1403.

134. Nedorostova L, Kloucek P, Kokoska L, Stolcova M, Pulkrabek J. Antimicrobial properties of selected essential oils in vapour phase against foodborne bacteria. Food Control. 2009;20:157–60.