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Role of Medicinal Plants and Herbs in Veterinary Medicine
Yang, W., Ke, C., Wu, W., Lee, R., & Tseng, Y. (2019). Effective Treatment of Bovine Mastitis with
Intramammary Infusion of Angelica dahurica and Rheum officinale Extracts. Evidence-Based Comple-
mentary and Alternative Medicine, 2019, 1–8. doi:10.1155/2019/7242705 PMID:31019541
Zenner, L., Callait, M. P., Granier, C., & Chauve, C. (2003). In vitro effect of essential oils from
Cinnamomum aromaticum, Citrus limon and Allium sativum on two intestinal flagellates of poultry,
Tetratrichomonas gallinarum and Histomonas meleagridis. Parasite (Paris, France), 10(2), 153–157.
doi:10.1051/parasite/2003102153 PMID:12847923
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Chapter 4
Plant Extracts With
Antibiotic Effect
Mona Luciana Gălăţanu
https://orcid.org/0000-0003-2623-3307
Titu Maiorecu University, Romania
Mariana Panţuroiu
https://orcid.org/0000-0002-9932-0463
Titu Maiorescu University, Romania
49
Mariana Popescu
Titu Maiorescu University, Romania
Carmen Marinela Mihăilescu
Titu Maiorescu University, Romania
ABSTRACT
This chapter tries to describe the most important plant extracts and their bioactive compounds which
determine the antibiotic activity. Pharmacological assays performed for each plant extract are presented, including the minimum inhibitory concentration (MIC) as the most used experimental method
to determine antimicrobial activity. Also, the effective associations between classic antibiotics and plant
extracts with antibacterial are presented. The mechanisms of action are deeply explained to the extent
that they are known and discovered by in vitro and in vivo studies. Plant-derived compounds have different mechanism of action as antibiotics. They can have other target sites than traditional antimicrobials and subsequently having different mechanisms of action against microbes. Ultimately, this chapter
tries to be an invitation to use plant extract as an alternative to chemical, synthetic antibiotics, or used
complementary, synergistic for better therapeutically results.
INTRODUCTION
Bacterial infections are a major cause of human pathologies. Massive use of antibiotics led to developing
DOI: 10.4018/978-1-6684-5129-8.ch004
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Plant Extracts With Antibiotic Eect
resistance against them, which is another problem affecting public health. To fight against the lack of the
new substances with antibiotic effect, and against the increasing antibiotic resistance, plants could be a
potential solution in the future. Medicinal plants produce a variety of secondary metabolites that have an
important role in adaptation to the environment, providing them with effective defense mechanisms to
control pests and pathogens. Plants provide a great biodiversity, including about 374,000 plant species, of
which about 290,000 of them have secondary metabolites. Among these natural compounds are essential
oils, flavonoids, coumarins, tannins, quinones, alkaloids, lectins, polypeptides, thiosuflinates and others,
that have potential therapeutic action to fight against bacteria (Kokoska et al., 2019; Alvarez-Martinez et
al., 2020). They have many advantages like lesser side effects, more patient approval, and are less costly.
Many in vitro studies have showed the antibacterial effect of some plant extracts, based on measuring
the minimum inhibitory concentration, which is the lowest concentration of a substance that inhibits 90%
of the bacterial growth, as the most used indicator of the antimicrobial efficacity (Drusano et al., 2004).
Scientific studies have been performed to verify the antibacterial potency of plants against all kinds of
bacterial cultures, including biofilms. Moreover, two plant extract products have received approval from
the U.S. Food and Drug Administration (FDA) as antibacterial drugs: Veregen, based on green tea leaf
extract, which contains epigallocatechin gallate, indicated for genital and perianal warts, and Fulyzaq or
Mytesy, extracted from the dragon’s blood, for the treatment of diarrhea in cases of patients with HIV
antiretroviral therapy (Wu et al., 2020).
For a better efficacy, in pharmacological studies plants are used as extracts. During extraction, the
active compounds from medicinal plants are separated from the other inactive components, based on
their solubility in different solvents. The methods of standard extraction are decoction, infusion, maceration, percolation, digestion, or Soxhlet extraction, and the final products obtained are decoctions,
infusions, macerates, essential oils, aromatic waters, tinctures, semisolid, and dried extracts. Chassagne
et al. (2021) noticed that among different plant extracts, crude extraction in methanol was the most used
type of extraction encountered in studies, while leaves were the main plant organ used for extraction.
The purpose of the chapter is to present the most important plant extracts with antibiotic effect, based
on their efficacy against bacteria, proved by recent, in vitro studies, together with their mechanism of
action, which can be used as promising alternative to common antibiotics.
BACKGROUND
Microbial resistance to antibiotics has led scientists to target new molecules to discover substances that
can fight bacteria. Plants are a huge and inexhaustible source of bio compounds with pharmacological
activities, including antibacterial. Plant extracts are used for centuries in different traditional medicines,
and nowadays included in various clinical studies for studying different therapeutically effects concerning human pathologies. Different yeasts and plant extracts were used since antiquity to treat infections.
For example, Egyptians used to apply mouldy bread to infected wounds. However, common bacterial
infections were the major cause of human death, and it was until 19
few antibacterial substances in action. Alexander Fleming accidentally discovered penicillin, in a culture of a Penicillium notatum mould, proved to be extremely effective against Staphylococcus bacteria.
The treatment with this first mass-produced antibiotic was hugely successful, and a huge discovery for
humankind, as it saved many soldiers’ lives in the Second World War, in the field and in hospitals.
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th
century that scientists discovered
Plant Extracts With Antibiotic Eect
Plants extracts are rich in many secondary metabolites such as polyphenols (flavonoids, quinones,
tannins, coumarins), terpenoids (from essential oils), alkaloids, isothiocyanates, glucosinolates, lectins
and polypeptides, which have been found in vitro to have antimicrobial properties against different types
of bacteria. Many studies have been conducted in different countries to prove the efficiency of phytochemicals for therapeutic treatments. Pancu et al. (2021) observed that “between 1986 and 2006, more
than 100 antimicrobial drugs were approved for clinical use, 75 being of plant origin”.
CHEMICAL STRUCTURE OF BIOACTIVE COMPOUNDS
Herbal antibacterial compounds can be divided into several categories, as phenolic compounds, quinones,
flavonoids, tannins, glucosinolates, thiosulphur compounds, lignans, terpenoids and alkaloids, as well
as another described below:
Phenolic and Polyphenolic Compounds
They are the most common secondary metabolites of plants; the term phenol defines phenyl ring compounds substituted with one or more hydroxyl groups, and the term polyphenols defines compounds
with at least two phenyl rings substituted with one or more hydroxyl groups, including their functional
derivatives. Constituents with diversified chemical structure, phenolic and polyphenolic compounds are
represented by simple phenols and benzoquinones, phenolic acids, stilbenes, hydroxycinnamic acids,
flavonoids, coumarins, lignans, anthraquinones, naphthoquinones. They are mainly found in conjugated
form with simple, acylated or protein-bound bases.
Simple Phenols and Phenolic acids
Some of the simplest phyto-compounds with antimicrobial effects are catechol and floroglucinol, characterized by the presence of two or three groups - OH, respectively, with toxic effects on microorganisms. Simple phenolic compounds often have alcohol, aldehyde, and carboxylic groups, such as eugenol
and vanillin, compounds well known for their antibacterial activity. Phenolic acids are derived from
cinnamic acid and are widespread compounds in the plant kingdom. Cinnamic acid is a precursor for
the synthesis of more complex phenolic compounds such as p-coumaric acid and caffeic acid. Phenolic
acids have antimicrobial potential due to the presence of numerous groups -OH or methoxy (-OCH3),
with cytotoxic effects on infectious agents. Caffeic acid in the form of 3- caffeoylquinic ester, known
especially as chlorogenic acid, has been shown to effectively inhibit the growth of bacterial pathogens,
Shigella dysenteriae and S. pneumoniae at MIC values between 20 and 80 μg / mL. (Lou et al., 2011).
Quinones
Quinones are 1,4-diceto-cyclohexa-2,5-dienic derivatives (p-quinones) or 1,2-diceto-cyclohexa-3,5dienics (o-quinones), with conjugated double bonds. Structurally, these compounds have carbonyl
groups grafted on a benzene ring (benzoquinone), on bi or polycyclic aromatic hydrocarbons, simple
(e.g., naphthoquinone, anthraquinone) or condensed (naphthodiantrone), or on the structure of terpenes.
Nitrogen heterocyclic compounds rarely have a quinone structure. The most common natural quinones
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Plant Extracts With Antibiotic Eect
are hydroxylated and are found in plants in reduced form (naphthohydroquinone), but in the extraction
process they hydrolyze and turn into naphthoquinones. These compounds can form irreversible complexes
with amino acids in proteins, thus causing antibacterial activity (Abad Martinez et al., 2005, Stern et al.,
1996, Castro et al., 2013). The 1,4-naphthoquinone has significant antibacterial activity in vitro against
gram-positive and gram-negative bacteria.
Flavonoids
They are natural polyphenols, type C6-C3-C6, characterized by the presence of the benzopyran nucleus
substituted with phenyl radical. Depending on the degree of oxidation of the molecule and the site of
phenyl insertion, there are several categories of flavonoid compounds, namely: flavones, flavonols,
flavanones, catechins, flavanonols, isoflavones, chalcones, anthocyanins. The diversity of these compounds is also explained by some structural chemical modifications such as hydroxylation, methylation,
acylation, glycosylation. Some flavonoids, such as hesperidin, hesperetin, naringin, and naringenin,
have antibacterial and antifungal activity. Relatively recent in vitro studies have shown the antibacterial
action of flavones such as kaempferol, luteolin, myricetin, including against MRSA (Xu & Lee, 2001).
The antibacterial activity is due to the ability of these compounds to affect protein synthesis and the
integrity of the bacterial cell wall and through synergism with some antibiotics (Tsuchiya et al., 1996;
Cowan, 1999).
Tannins
They are derived from polyphenol carboxylic acids or phenyl benzopyran. Structurally, they are hydrolysable tannins and proanthocyanins (condensed tannins). Hydrolysable tannins are esters of gallic acid
and ellagic acid or their derivatives with carbohydrates (glucose or another oasis) or a cyclitol. Proanthocyanins are polymers of flavan-3-ols (e.g., catechin) and flavan 3,4-diols bound by an interflavonoid
bond that is not hydrolysable. Tannins have the ability to complex with proteins by ionic reaction and
/ or hydrogen bonds and also by covalent bonds. Antibacterial action is also based on this mechanism,
especially against gram-negative germs (Haslam, 1996; Stern et al., 1996; Cowan, 1999).
Lignans
Lignans and neolignans are composed of great structural diversity and promising antimicrobial activity.
Important for therapy are components with the structure of tetrahydrofuran, such as 8-hydroxypinoresinol.
This compound isolated from the bark of Strombosia grandifolia is very active against S. pneumoniae,
E. coli, S. aureus and S. typhi (Ekalu et al., 2019). Carinol, a lignan isolated from Carissa species, espe-
cially stems and roots, showed considerable antimicrobial activity against four bacteria, P. aeruginosa, E.
coli, Staphylococcus aureus and Bacillus subtilis, with a MIC <1.25 mg / mL (Kaunda & Zhang, 2017).
Five lignans (secoisolariciresinol, pinoresinin, eudesmin, lariciresinol and lariciresinol-4-methyl ether)
isolated from Araucaria araucana (Mol.) showed significant antibacterial activities, the most sensitive
being Gram-positive (Céspedes et al., 2006).
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Plant Extracts With Antibiotic Eect
Glucosinolates and Thiosulfinates
Glucosinolates are a group of compounds whose structure comprises a “p-D-thioglucose” group, a “sulfonated oxime” moiety and a variable side chain derived from methionine, tryptophan, or phenylalanine.
When plant tissue is damaged, glucosinolates are hydrolyzed by the endogenous enzyme “myrosinase”
or intestinal microflora after ingestion, releasing a range of degradation products, including biologically
active isothiocyanates (Mithen et al., 2010). The isothiocyanates resulting from the enzymatic degrada-
tion of synigrozide, sinalboside, glucobrasicin act as an antibiotic against gram-positive and negative
bacteria. Cysteine sulfoxides (whose prototype is aliin) by cutting or crushing under the influence of the
enzyme aliinase are transformed into esters of thiosulfinic acids, whose prototype is allicin. The antibiotic
effect is due to the alkylsulfinates formed from sulfoxides, while the alkylsulfides and alkenylsulfenic
acids have mainly bacteriostatic action.
Terpenoids and essential oils
Terpenoids are products of secondary plant metabolism, the main constituents of essential oils, secreted
in specialized plant tissues. They are composed of isoprene units (C
monoterpenes (C
), sesquiterpenes (C15), diterpenes (C20), etc., depending on the number of forming
10
units (Cowan, 1999). Terpene compounds may be hydrocarbons (myrcene, limonene, terpene, pinene,
bisabolene, caryophyllene) or oxygenated derivatives including alcohols (linalool, nerol, geraniol, citronellol, terpineol, menthol, borneol, bisabolol, farnesol), phenols, carvacrol, thymol, eugenol), aldehydes
(geranium, citral and citronellal), ketones (tagetone, menthone, carvone, thuione, camphor) or ethers
(eucalyptol, linalool oxide) and esters (linalyl acetate, menthyl acetate). Depending on the antibacterial
coefficient, the compounds with the best activity are phenols, followed by methyl ethers, monoterpenic
aldehydes, monoterpenic ketones. The antibacterial properties of these compounds are due to their ability
to block the proliferation of pathogens by direct neutralization or by neutralizing their toxins.
) n and can be classified into
5H8
Prevalence of Antibiotics in Plants
Chassagne et al. (2021) analyzed the antibacterial activities of 958 plants from the literature published until
2019. The authors noticed that “antibacterial effect is found in 51 of 79 vascular plant orders throughout
the phylogenetic tree. Most of them are reported within eudicots, with the bulk of species being asterids, while monocotyledons have poor antibacterial activity” (Chassagne et al., 2021). The Lamiaceae,
Fabaceae and Asteraceae families were the most represented, while Cinnamomum verum, Rosmarinus
vulgaris and Thymus vulgaris were the most frequent species studied for their antibacterial action.
Mechanism of Action
Regarding the intrinsic mode of action of antibacterial bio compounds, Ginovyan et al. (2017) emphasized
that they “could have other target sites than traditional antimicrobials and subsequently having different
mechanisms of action against microbes”. Among the ways these bio compounds act as antibacterial are
the disrupting of microbial membranes, impairing the cellular metabolism, inhibiting the biofilm formation, reducing the bacterial capsule production, controlling quorum-sensing, or reduction of the microbial
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Plant Extracts With Antibiotic Eect
toxin production (Ginovyan et al., 2017). Al Sheikh et al. (2020) mention that “essential oils from parsley,
lovage, basil and thyme disrupt the physiological status of the bacterial cell by causing an increase in
cell permeability, leakage of cell constituents, alterations in bacterial cell wall and cell membrane, ATP
loss, inhibition of protein synthesis, pH disturbance, intracytoplasmic damage, DNA damage and inhibition of quorum sensing among bacteria” (Al Sheikh et al., 2020). Regarding the mechanism of action
of cinnamon and its constituents, Vasconcelos et al. (2018) noticed that ” inhibit bacteria by damaging
cell membrane; altering the lipid profile; inhibiting ATPases, cell division, membrane porins, motility,
and biofilm formation; and via anti-quorum sensing effects” (Vasconcelos et al., 2018). An extensive
review performed by Álvarez-Martínez et al. (2021) on the full spectrum of plant antimicrobial agents
discovered from 2016 to 2021, proved that the most frequent mechanism of antimicrobial effect is the
interruption of plasma membrane of bacteria.
It is also important to highlight the synergistic mechanism of herbal compounds with the classical
antibiotics, due to decreasing the bacterial resistance, as shown by numerous studies.
PLANTS WITH ANTIBIOTIC PROPERTIES
Mentha piperita L.
Plant Description
Peppermint is a hybrid between two species: Mentha spicata L. (spearmint) and Mentha aquatica L.
(water mint) and is a perennial plant from the Lamiaceae family. It is worldwide cultivated as a medici-
nal specie for its anti-inflammatory, antidiarrheic, antispastic, analgesic, antifungal, antimicrobial, and
central nervous system excitation effects and used for the treatment of a wide range of digestive maladies,
musculo-skeletal pains, respiratory disorders, and various infections. The essential oil of peppermint
contains mainly menthol, 1,8-cineole, limonene, β-myrcene, β-caryophyllene, menthone, isomenthone,
pulegone, carvone, menthyl acetate, and menthofuran (Akhtar et al., 2017). Peppermint also has bitter
substances, caffeic acid, flavonoids, and tannins.
Biological Activities
Several studies demonstrated a significant antibacterial activity for peppermint essential oil. Abolfazl
et al. (2014) noticed an important antibacterial activity of the essential oil, due to the monoterpenes as
menthol and menthone, which exerted MICs with an average of 0.5–8 μg/mL in Staphylococcus aureus,
P. aeruginosa, Streptococcus pneumoniae, E. coli, Salmonella typhi and Klebsiella pneumoniae strains.
The essential oil from M. piperita exhibited antimicrobial effect against Salmonella enterica, with an
inhibition zone of 9.00 ± 1.00 mm (Valková et al., 2021), on S. aureus, P. aeruginosa, E. coli, and K.
pneumoniae (Osanloo et al., 2020), and also against Salmonella typhius, Staphylococcus epidermititis,
S. aureus, B. subtilius, P. aeruginosa, and Klebsiella pneumonia cultures (Saba & Anwar, 2018). The
other biological compounds from peppermint, as phenolics exert antibacterial activity, too. Mahady et
al. (2005) found that the methanolic extract of mint was active on Helicobacter pylori strains, with a
minimum inhibitory concentration (MIC) of 25–100 μg/mL. The ethanolic extract of peppermint which
contains gallic, p-coumaric chlorogenic, neochlorogenic, ferulic, and rosmarinic acids, epicatechin,
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Plant Extracts With Antibiotic Eect
Figure 1. Chemical Structure of Some Bio Compounds with Antibiotic Effect
quercetin-3-rutinoside and quercetin, also inhibited the growth of Asaia bogorensis, and A. lannensis, as
Antolak et al. (2018) showed. In vitro efficacy of the association M. piperita essential oil with different
classic antibiotics was evaluated against numerous Gram-positive and Gram-negative bacteria, using
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Plant Extracts With Antibiotic Eect
Figure 2. Schematic Presentation of the Main Mechanisms of Antibacterial Action of Plants (Pancu et
al., 2021)
checkerboard microdilution method. The synergistic effect of M. piperita essential oil with gentamicin
inhibited the growth of Pseudomonas aeruginosa and Klebsiella pneumoniae. Associations of ampicil-
lin with M. piperita essential oil showed also a strong synergistic effect on Escherichia coli and Bacil-
lus subtilis strains (Rosato et al., 2018). The peppermint essential oil act as antibacterial effects with a
mechanism of disrupting the structure of membranes, which leads to the loss of integrity and elevated
cell permeabilization, and inhibition of RNA and protein synthesis due to the hydroxyl group in phenol
compounds (Tafrihi et al., 2021).
Figure 3. Antimicrobial mechanisms of herbal agents
(Parham et al., 2020)
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Plant Extracts With Antibiotic Eect
Salvia officinalis L.
Plant Description
Sage is a perennial plant from the Lamiaceae family, native to the Mediterranean region, but has been
naturalized worldwide, especially in Europe and North America. In the traditional European medicine,
S. officinalis is used to treat excessive sweating and hot flashes associated with menopause, as a remedy
for digestive disorders accompanied by bloating, cramps, to improve memory and age-related cognitive
impairment, or inflammation of the throat and skin.
Biological Activities
Several studies support the antimicrobial effects of S. officinalis. S. officinalis essential oil has a signifi-
cant inhibitory effect against Gram-positive and Gram-negative bacteria such as Aeromonas hydrophila,
Escherichia coli, Klebsiella oxytoca, Klebsiella pneumonia, Pseudomonas morgani, Salmonella species,
Shigella sonei and Bacillus subtilis. Data from the literature report values of minimum inhibitory con-
centration (MIC) between 12.5-225 μg/mL (Golestani et al., 2015, Ghorbani et al., 2017, Santos et al.,
2017). The antibacterial potential of S. officinalis essential oil can be attributed to the high content of
monoterpenes such as thujone, camphor, 1,8-cineole, α- and β-pinene, compounds active against a wide
range of microorganisms, including Gram-positive and Gram negative. Thujone, camphor, 1,8-cineole,
and carvacrol have been shown to have antibacterial effects against Aeromonas hydrophila, Aeromonas
sobria, B. mega therium, B. subtilis, B. cereus, and Klebsiella oxytoca (Hamidpour et al., 2014; Fourn-
omiti et al., 2015). However, to explain the biological activity of sage oil, the synergistic effects of its
constituents must be taken into account. In vitro antibacterial activity tests have shown that Gram-positive
bacteria are more sensitive to sage essential oils than Gram-negative bacteria, which can be attributed to
cell membrane structure (Nikaido & Vaara, 1985; Nostro et al., 2000). Recent studies have investigated
the antibacterial potential of ethanolic extracts of Salvia officinalis leaves and reported a MIC of 62.5
and 300 μg/mL, respectively, against Streptococcus pyogenes and Staphylococcus aures. Another in vitro
study showed that aqueous sage extract caused significant antibacterial activity against Bacillus mycoides,
Bacillus subtilis, Enterobacter cloacae and Proteus sp. (Hamidpour et al., 2007). The main constituents
responsible for the antibacterial activity of these extracts are rosmarinic acid, quercetin, ellagic acid,
chlorogenic acid (Wijesundara and Rupasinghe, 2019; Ghorbani & Esmaeilizadeh, 2017). The antibacterial profile of S. officinalis was also studied by Oliveira et al. (2019), by testing the glycolic extract
against clinical isolates with Streptococcus mutans, Staphylococcus aureus, S. epidermidis. The authors
concluded that at a concentration of 50 mg / mL, this extract completely eliminates strains without toxic
effects. Horiuchi et al. (2007) reported that the crude leaf extract of S. officinalis exerts antimicrobial
activity against MDR bacteria, such as vancomycin-resistant enterococci, penicillin-resistant Streptococ-
cus pneumoniae and methicillin-resistant Staphylococcus aureus. The effective antibacterial compounds
have been identified as ursolic acid and oleanolic acid, and the minimum inhibitory concentration (MIC)
was 4 µg/mL for ursolic acid and 8 µg/mL for oleanolic acid. The two pentacyclic triterpene compounds
also showed bactericidal activity against vancomycin-resistant enterococci at concentrations twice as
high as MIC. No compounds showed antibacterial activity against tested Gram-negative bacteria (E.
coli, P. aeruginosa, S. marcescens). Carnosic acid and its derivative carnosol (picrosalvin), two other
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