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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_6035_Библиотеки_им_академика_М_И_Перельмана.pdf
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CHAPTER 4
Natural Products with Antimicrobial Properties
MARÍA MELISSA GUTIÉRREZ PACHECO1, HERIBERTO TORRES MORENO2,
RICARDO SALOMON TORRES1, LUIS ALBERTO ORTEGA RAMÍREZ
JULIO CÉSAR LÓPEZ ROMERO
1
2
2,*
ABSTRACT
Bacterial infections rank among the primary contributors to morbidity and mortality worldwide. In recent years, there has been a noteworthy rise in deaths generated each, attributable
to bacteria’s ability to resist the effect of conventional antimicrobials, causing them to lose
their effectiveness. Therefore, searching for new strategies that can represent a feasible and
effective treatment alternative is necessary. In this context, products of natural origin could
represent an alternative since, historically, populations have used them to treat various
health conditions, such as bacterial infections. Recent research has focused on analyzing
sources of natural origin to investigate and confirm these biological effects scientifically. It
has been shown that these sources have stood out for having an antimicrobial effect using
in-vitro, in-silico, and in-vivo methods against clinically relevant pathogens. These effects
have been associated with the chemicals present, which sometimes have been shown to
have low cytotoxicity against healthy cells and recognize satisfactory parameters for drug
development. Previous research has shown that products of natural origin offer a valuable
resource for extracting chemical compounds with antimicrobial effects and could represent
a feasible option for the development of antimicrobial therapies.
1,*
, and
*Corresponding author
4.1 INTRODUCTION
Antimicrobial resistance represents a public health concern, constituting one of the main
causes of death worldwide (Razzaque, 2021). The loss of efficacy of commonly used
antimicrobial therapies in the clinical area is associated with the overuse and misuse of
antibiotics (Gajdács et al., 2021). This becomes a challenge for health since bacterial
56
infections are more difficult to treat. Bacterial resistance increases the risk to promote a
critical evolution in patients, such as sepsis and death (Makabenta et al., 2021).
It is estimated that infections caused by antimicrobial-resistant bacteria cause nearly
700,000 deaths yearly worldwide, and the number tends to increase every year (Romandini
et al., 2021). Additionally, the World Health Organization (WHO) estimated that if the
problem of antimicrobial resistance continues to rise, it could become the leading cause of
death worldwide by the year 2050, producing more than 10 million deaths yearly (Naylor et al.,
2018). Due to the growing increase in antibiotic-resistant strains, the WHO published a list of
pathogens based on their priority. Critical priority includes the carbapenem-resistant strains
Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii. In the high
priority category, there are vancomycin-resistant Enterococcus faecium, methicillin-resistant
Staphylococcus aureus (MRSA), clarithromycin-resistant Helicobacter pylori, uoroquinolone-
resistant Campylobacter spp., uoroquinolone-resistant Salmonella, and uoroquinolone
and cephalosporin-resistant Neisseria gonorrhoeae. The medium priority category includes
penicillin-nonsusceptible Streptococcus pneumoniae, ampicillin-resistant Haemophilus
inuenzae, and uoroquinolone-resistant Shigella spp. High priority includes Staphylococcus
aureus (methicillin-resistant, MRSA), Enter ococcus faecium, Helicobacter pylori vancomycin-
resistant, Salmonella clarithromycin-resistant, Campylobacter spp. uoroquinolone-resistant,
and Neisseria gonorrhoeae uoroquinolone and cephalosporin-resistant. Medium priority
includes Streptococcus pneumoniae penicillin-nonsusceptible, Haemophilus inuenza
ampicillin-resistant, and Shigella spp. uoroquinolone-resistant (WHO, 2017).
Recently, it has been observed that a factor associated with resistance, chronicity, and
pathogenicity is the ability of pathogenic bacteria to produce biolms, which are characterized
as communities of microorganisms embedded in a matrix of exopolysaccharides, mainly
composed of water, proteins, carbohydrates, and genetic material (Srinivasan et al., 2021).
This structure promotes a community with antimicrobial resistance and availability to develop
on biotic or abiotic surfaces (Amankwah et al., 2021). In this sense, it is estimated that these
structures are 10–1000 times more resistant than planktonic cells. In turn, biolms are estimated
to cause more than 80% of infections produced at the hospital level (Borges et al., 2017).
Based on the above, it is evident that it is necessary to search for new antimicrobial
treatments that are effective and may represent a natural alternative in the treatment
against bacterial infections caused by resistant bacteria. In this sense, it is known that
several cultures have used natural products throughout the years to treat different diseases
(Atanasov et al., 2021). About 80% of the world population is estimated to use natural
products as main treatments for different health conditions (Nguyen et al., 2021). In
recent years, scientic research has focused on verifying the traditional uses of these
natural products and understanding the mechanism of action. One of the biological
activities widely analyzed in natural products is their antimicrobial effect, where it has
been shown that these compounds can inhibit the growth of clinically relevant pathogenic
microorganisms, including antibiotic-resistant clinical isolates. In addition to the above,
some studies have isolated and characterized the chemical compounds responsible for
these effects (Chassagne et al., 2021; Feitosa et al., 2022). In turn, it has been observed that
these treatments have shown effectiveness in vivo, some of them even being analyzed in
57
clinical trials (W agenlehner et al., 2018). These natural antimicrobial sources can emer ge as
alternate treatments for bacterial infections produced by resistant and nonresistant bacteria.
4.2 PLANTS AS ANTIMICROBIAL AGENTS
The utilization of plants in disease treatment dates back to the origins of human existence,
playing an essential role in the healthcare of world’s population (Aleksic Sabo and
Knezevic, 2019). Plants are rich in various bioactive compounds which are the products
of their secondary metabolism, and display an enormous structural diversity. Compounds
such as phenylpropanoid, isoprenoid, alkaloid, or fatty acid/polyketide biosynthesis
pathways are synthesized in response to different biotic or abiotic stresses (Chandran et al.,
2020). Often, it is the secondary metabolites that account for the biological properties of
certain plant species utilized worldwide for diverse purposes, including the treatment of
infectious diseases (Ghareeb et al., 2015). They are gaining more attention because they are
affordable, accessible, eco-friendly, and highly effective as compared to costly synthetic
drugs (Chandran et al., 2020).
Bioactive compounds found in plants exhibit various biological activities, which includes
anti-inammatory effects, antioxidant, antiparasitic, and antimicrobial as demonstrated
through in-vitro and in-vivo studies. These compounds include polyphenols (avonoids,
phenolic acids, stilbenes, anthocyanins, lignans, tannins), alkaloids, organosulfur compounds,
and coumarins (Manandhar et al., 2019) (Figure 4.1). The variety of these compounds found
in plants depends upon different factors, for example, the source (fruit, vegetable, herb, and
medicinal plant) (López-Malo et al., 2020), the part of the plant (seed, ower, bark, root, peel,
stem, and leaf) (Bělonožníková et al., 2023), the obtention method (extract or essential oil
(EO) (Bączek et al., 2017), the extraction solvent (Hossan et al., 2018), and so on.
FIGURE 4.1 Classes of bioactive compounds found in plant tissues.
⏎
58
Many sources of plant-derived antimicrobials have been reported in the scientic
literature. Some of the sources include extracts, EOs, or isolated compounds from spice-
bearing plants (e.g., bark, leaves, stems, petals), medicinal plants (owers, steam), fruit,
and vegetables (pulp, skin, seed, juice), as well as the by-products generated from their
industrial processing (Table 4.1).
TABLE 4.1 Occurrence of Antimicrobial Compounds in Some Plants
Plants Along with the Source
of Antimicrobial Compounds
Malus domestica (seed)
Origanum vulgare EO (leaf) Terpenoids (carvacrol, thymol, p-cymene,
Vitis vinifera (fruit)
Elettaria cardamomum extract
(fruit)
Ocimum basilicum EO Thymus
algeriensis EO (entire plant)
Chlorophytum borivilianum
extract
Vitis vinifera var. Red Globe
(stem extract)
Punica granatum (peel extract)
Artemisa campestris EO
(seed-bearing parts)
Thymus vulgaris EO
(entire plant)
Antimicrobial Compounds References
Phenolic acids (protocatechuic acid, coumaric
acid, ferulic acid, chlorogenic acid, caffeic acid)
Flavonoids (quercetin derivatives, (+)-catechin,
(–)-epicatechin) Proantocyanidin (procyanidin
B2) Dihydrochalcone (floridzina)
γ-terpinene)
Stilbene (resveratrol) Anthocyanins (2-cyanindin3-glucoside, delphinidin-3-glucoside, 3-malvidin)
Flavonoid (quercetin, myricetin, laricitrin,
kaempferol, syringetin, isorhamnetin, epicatechin)
Polyphenolic acids (caffeic acid, rosmarinic
acid, ferulic acid) Flavonoids (quercetin,
kaempferol, chrysin, galangin, pinocembrine)
Terpenes (linalool, linalyl acetate) Terpenoids
(α-terpinyl acetate, neryl acetate, α-pinene)
Saponins Alkaloids Flavonoids Chandran et al. (2020)
Phenolic acids (ferulic acid, gallic acid, caffeic
acid, chlorogenic acid) Flavonoids (catechin, rutin)
Phenolic acids (chlorogenic acid, gallic acid,
ferulic acid, caffeic acid, p-cumaric acid)
Flavonoid (catechin, rutin)
Terpene (β-pinene, α-pinene, limonene)
Terpenoid (o-cymene, spathulenol)
Terpenes (thymol, 1,8-cineole, γ-terpinene,
p-cymene, α-terpinene)
⏎
Xu
et al. (2016)
Sakkas and Papadopoulou
(2017)
De Sales et al. (2018);
Chandran et al. (2020)
Moulai-Hacene
(2020)
Rezzoug
Vázquez-Armenta et al.
(2017)
Cruz-Valenzuela
(2022)
Al Jahid
Aljabeili et al. (2018)
et al.
et al. (2019)
et al.
et al. (2017)
Several studies showed the antimicrobial activities of plant extracts by in-vitro tests
against human pathogens (Table 4.2). For example, Hossan et al. (2018) evaluated the
antibacterial activity of ethanol, hexane, and ethyl acetate extracts from 18 medicinal
plants against the clinically relevant pathogens as Escherichia coli, MRSA, Enterococcus
faecalis, P. aeruginosa, K. pneumonia, and A. baumannii. Authors found that hexane
extract of bark of Cinnamomum cassia L. inhibited the growth of all tested bacteria at
concentrations below 100 µg/ml.
59
As mentioned above, the antimicrobial activity of plants varies depending upon different
factors, including the place of origin, variety , season, and part of the plant, among others. T o
demonstrate this, a study evaluated the antibacterial activity of Eucaliptus camaldulensis,
a medicinal plant used in traditional medicine. EOs from bark and leaves were evaluated
against Gram-positive and Gram-negative bacteria. Mainly, EOs isolated from leaves of
E. camaldulensis from Iran inhibited the growth of K. pneumoniae, P. aeruginosa, E. coli,
and A. baumannii at minimal inhibitory concentrations (MIC) of 0.05, 0.2, 0.15, and 0.1
mg/ml, respectively. In contrast, aqueous extracts of leaves of E. camaldulensis procured
from Nigeria inhibited Salmonella typhi, E. coli, and S. aureus at 50 mg/ml (Aleksic Sabo
and Knezevic, 2019).
Bělonožníková et al. (2023) evaluated the antibacterial activity of stems, leaves, owers,
and roots of Origanum vulgare L. and Agrimonia eupatoria L. against P. aeruginosa.
Results showed that ethanolic extracts derived from O. vulgare owers and roots exhibited
the most potent antimicrobial activity, with MIC50 values of 7 and 4 mg/ml, respectively.
De Zoysa et al. (2019) evaluated the antimicrobial activity of Epaltes divaricate extracts
against S. aureus. Aqueous, ethanol, and hexane extracts showed maximum inhibition
zones of 7.4, 16.3, and 13.7 mm with MIC of 1.2, 0.48, and 1.6 mg/ml, respectively.
In order to assess the viability of using plants as a therapeutic approach against infections caused by human pathogens, it was essential to carry out in-vitro research and in-vivo
experiments by administering plant products to animal models, and eventually conducting
human clinical trials (Sathianarayanan et al., 2022). The potential of plant extracts to
inhibit human pathogens was evaluated in randomized clinical trials. Stange et al. (2017)
probed the combination of Tropaeolin majoris herba and Armoracia rusticana radix and
compared with the antibiotic cotrimoxazole in adult patients (average age of 38.5 years;
90% female) diagnosed with acute uncomplicated cystitis. Adults were treated with ve
tablets of herbal combination four times a day (for 7 days) or the antibiotic two times a day
for 3 days. Following the treatment, 90% of patients in the herbal treatment group were
symptom-free by day 15, while the antibiotic group achieved 100% symptom-free status.
The herbal treatment group experienced mild side effects in three patients (decreased
appetite, dyspepsia, and headache), while the antibiotic group had ve patients with side
effects (diarrhea, headache, disturbance in attention, gastrointestinal pain, etc.). No severe
side effects were reported in either group, and both treatments demonstrated comparable
results.
In another study, Wagenlehner et al. (2018) conducted a randomized and controlled
clinical trial to evaluate a herbal therapy Canephron® N (BNO 1045), to treat uncomplicated
urinary tract infections (UTI) compared with fosfomycin trometamol (FT). The participants
in the study were females between the ages of 18 and 70, presenting typical symptoms of
recently diagnosed UTI. Patients received tablets containing 18 mg of rosemary (Rosmarini
folium) leaves, 18 mg of herb (Centaurii herba), and 18 mg of lovage (Levistici radix) root.
Two tablets were administered orally, three times daily, before or after meals, for 7 days.
On the other hand, a dose of 5.631 g of FT (equivalent to 3 g of fosfomycin) was dissolved
in 100–200 ml of water and consumed immediately as a single dose on day 1. Results
showed that with a 15% noninferiority margin, the herbal therapy was noninferior to FT
in treating UTIs. Additionally, adverse events were comparable between the two groups,
TABLE 4.2 In-Vitro Studies of the Antimicrobial Activity of Plant Extracts Against Clinically Relevant Bacteria
Plant Extraction Solvent Concentration Microorganisms Tested Effect References
Tecomella undulata
Momordica charantia
Hibiscus sabdariffa
Litsea cubeba L. EO
Cinnamomumcassia EO
Zingiber officinale
Triumfetta welwitschii root
Allium sativa EO
Thymbra spicata L. extract
Pithecellobium dulce
(Roxb.) Benth. Securidaca
longepedunculata Fresn.
Cryptolepis sanguinolenta
(Lindl.) Schlt
Thymus vulgare EO
Salvia officinalis EO
Oreganum vulgare EO
Cornus mas
Oxalis corniculata
Ethanol 0.62 mg/ml
Ethanol 1.25 mg/ml Growth inhibition
Methanol:water (80:20) 50–100 mg/ml Viability inhibition Abdallah (2016)
– 1.04 mg/ml Growth inhibition Membrane
– 19.53 µg/ml
Methanol:water (70:30) 10 µg/ml Growth inhibition Chakotiya et al. (2017)
Dichloromethane:methanol
(50:50)
– 100 mg/ml Growth inhibition
Water:ethanol:petroleum
ether
Ethanol:water (70:30) 3.125–100 mg/ml Growth inhibition Synergy
– 11.34 mg/
– 10% (v/v)
Methanol 25 mg/ml Growth inhibition
100 μg/ml Growth inhibition Membrane
50 mg/ml
l 240 mg/
l 102.7 mg/l
A. baumannii
P. aeruginosa
K. pneumoniaeae
E. coli
⏎
Growth inhibition Valizadeh
Hao
et al. (2021)
and cell wall damage
Intracellular leakage
Growth inhibition El Atki et al. (2019)
Mombeshora and
disruption
Cell wall damage
Increased membrane
permeability
Growth inhibition Haroun and Al-Kayali
with antibiotics: Amikacin/P.
dulce Amikacin/C.
sanguinolenta Imipenem/P.
dulce Imipenem/C.
sanguinolenta
Growth inhibition Fournomiti et al.
Viability inhibition Loss of
membrane integrity Inhibition
of DNA gyrase activity
Mukanganyama
(2019)
Lestari
et al. (2018)
(2016)
Toudji
et al. (2018)
(2015)
EfenbergerSzmechtyk
(2021)
Manandhar et al.
(2019)
60
et al. (2020)
et al.
TABLE 4.2
Plant Extraction Solvent Concentration Microorganisms Tested Effect References
Hibiscus sabdariffa
Zingiber officinale EO
Aloe barbadensis
Cinnamomum zeylanicum
bark EO
Jatropha gossypifolia EO
Thymbra spicata L.
Cymbopogon flexuosus EO
Hibiscus rosa-sinensis L.
Hibiscus sabdariffa L.
Acacia nilotica EO
Litseamollis Hemsl. EO
Opuntia ficus indica
(Continued)
Ethanol
Water
– 2–4 mg/ml Growth inhibition Viability
Hexane 6.25 mg/ml
– 0.15–2.5 μl/ml
– 0.05 mg/ml Viability inhibition Okoh et al. (2016)
Water:ethanol:petroleum
ether
– 0.8 mg/ml Growth inhibition Sharma
Ethanol 0.2–0.25 mg/ml
Water 9.18–16.68 μg/
Ethanol:water (80:20) 1.56–3.12 mg/ml
– 0.05% Cell envelope damage
Ethanol:water (1:4) 3.35%
5% (w/v) Growth inhibition Cased
membrane hyperpolarization
Reduced internal pH
inhibition Cell membrane
damage
Growth inhibition Dharajiya et al. (2017)
Growth inhibition Saki et al. (2020)
Growth inhibition Haroun and Al-Kayali
Growth inhibition Viability
inhibition Affected biofilm
formation and urease activity
Growth inhibition Synergy
with clarithromycin and
metronidazole
Growth inhibition
Cell membrane damage
Electrolyte, nucleic acid, and
alkaline phosphatase leakage
Growth inhibition Welegerima and
25 mg/ml
1.25–1.5 mg/ml
ml
S. macerens
E. faecium
S. aureus
H. pylori
Salmonella spp.
S. pneumoniae
Gonelimali
(2018)
Wang
et al. (2020)
(2016)
et al. (2020)
Ngan
et al. (2021)
Hassan et al. (2016)
Sadiq et al. (2017)
Cai et al. (2019)
Zemene (2017)
61
et al.
62
with gastrointestinal disorders occurring in the FT group and pyelonephritis reported in the
herbal medicine group. Authors concluded that herbal treatment could reduce outpatient
use of antibiotics and signicantly impact antimicrobial strategy.
Thyme EO was administered to hospitalized COVID-19 patients to reduce disease
symptoms. The study was divided into the thyme-receiving group and the control group.
Both groups received routine medications, and the treatment group additionally received
5 ml every 8 h for 7 days. The thyme-receiving group showed a signicantly higher
improvement rate than the control group. Furthermore, 85–97.5% of patients showed
reduced cough, chest pain, dyspnea, muscular pain, headache, and fatigue compared to
the control group (Sardari et al., 2021). Similarly, Xiong et al. (2020) conducted a study
to assess the effectiveness of combining Xuanfei Baidu decoction (herbal medicine) with
conventional drug treatment for treating COVID-19. Patients aged between 18 and 75
years with COVID-19 were randomly divided into two groups: one group received herbal
treatment along with conventional medicine (n = 22), while the other group received only
the conventional medicine (n = 20). Both groups received conventional medicine for 1
week, while the treatment group received additional Xuanfei Baidu decoction. Results
showed a signicant disappearance of cough, fever, fatigue, and loss of appetite in the
group that received the herbal medicine. Additionally, the number of white blood cells
and lymphocytes returned to normal parameters. Meanwhile, a signicant reduction of
C-reactive protein and erythrocyte sedimentation rate in the experimental group was
observed.
In a study involving subjects with gingivitis, a polyherbal mouthwash comprising
5% extracts of Zingiber ocinale, Rosmarinus ocinalis, and Calendula ocinalis was
compared against chlorhexidine and a placebo mouthwash. This randomized and doubleblind trial consisted of two groups of 20 subjects who were directed to use the mouthwash
twice daily , after breakfast and dinner , for a duration of 30 s over 2 weeks. At the end of the
trial, polyherbal mouthwash showed similar results to chlorhexidine in reducing gingival
inammation, the severity of gingival bleeding, and plaque formation in the subjects
(Mahyari et al., 2016).
In another study, the anti-Helicobacter pylori activity of the methanolic extract of
Bryophyllum pinnutum was assessed using a mouse model. Swiss mice were inoculated
with an H. pylori suspension and treated with 125, 250, and 500 mg/kg of the B. pinnutum
extract or ciprooxacin (500 mg/kg) for 7 days. After treatment, H. pylori bacterial load
and colonization of mice stomach were determined at 1 and 7 days. The extract showed
a MIC and minimal bactericidal concentration (MBC) of 32 and 256 μg/ml and the load
of H. pylori in gastric tissue was reduced from 100% to 17%. Also, bacterial load after B.
pinnutum treatment decreased to 85.91 CFU, compared to untreated infected mice (11,883
CFU) and ciprooxacin-treated mice (25.74 CFU) (Sathianarayanan et al., 2022).
The resistance and prevalence of microorganisms in the clinical environment are often
attributed to their ability to adapt and respond to different types of stress. One of the
mechanisms that bacteria use is the formation of biolms. Biolms are conglomerates of
microorganisms embedded in a self-produced matrix of extracellular polymeric substances
composed mainly of carbohydrates, proteins, lipids, and DNA (Gutierrez-Pacheco et al.,
2019). This matrix makes biolms highly resistant and challenging to eradicate.