D. Sheikhi‡ * Guilan University of Medical Sciences, Department of Pharmacognosy, School of Pharmacy, Research and Development Center of Plants and Medicinal Chemistry, Rasht, Iran ** Shiraz University of Medical Sciences, Medicinal Plants Processing Research Center, Shiraz, Iran † Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran ‡ Regulations (GCP/ICH), Pharmaceuticals, Denmark
Due to presence of secondary bioactive metabolites, natural compounds are considered a major source of new active molecules that can be developed as new drugs. Infectious diseases, and mainly the common respiratory infections, are major challenges to the current chemotherapy systems and, therefore, there is a requirement to find new compounds with therapeutic potential. The volatile natural compounds and essential oils are the main treasure agents in the natural compounds with antibiotic potential. The present chapter reviews natural traditional remedies used in the treatment of respiratory infections with the emphasis on antibacterial, antiviral, and antiinflammation activities of the volatile natural compounds (essential oils, etc.), and provides a brief view in some of structural activity relationships between antibacterial potencies and chemical structures of the essential oil’s constituents.
Referring to infectious disease, respiratory tract infections engage with all surfaces in the respiratory tract. Based on the infected zone, respiratory infections can be categorized into upper tract infection (URI or URTI) and lower tract infection (LRI or LRTI). Each involves different parts of the respiratory tract infections, which vary in type and severity of microorganisms. Although there are different types of respiratory tract infections, the acute form in the upper respiratory tract infection predominates and includes several complications, such as sinusitis, pharyngitis, epiglottitis, laryngitis, and tracheitis. On the other hand, lower respiratory tract infection (LRTI) includes both acute and chorionic types, such as pneumonia and bronchitis. Based on pathogenicity, bacterial and viral pathogens are the most common microorganisms in both types (ie, LRTI and URTI). Moreover, infection distribution leads to varieties based on the patient’s age; for example, acute respiratory infections pose severe problem in childhood, which mainly occur in upper respiratory tract. Although the bacterial pathogens play a significant role in intensifying LRTIs, the major acute respiratory infections occur in upper respiratory tract, in these cases viral pathogens are the primary common pathogens, including influenza A and B, parainfluenza (type 1 and 3), adenovirus, and respiratory syncytial virus. Some of the common pathogens of the respiratory tract are listed in Table 16.1. Pathogen biodiversity, complexity, and mixed infections in many cases of respiratory tract infection have generated several problems for the treatment of respiratory infections. For example, various bacterial pathogens are encountered in several cases of viral infections. Therefore, the treatment of respiratory infections is a complex therapy which consists of several chemotherapy strategies.1–3 Antiviral (the same as antibacterial medication) is used to control the treatment and prevention of respiratory infections.
Some of the Common Pathogens Involved in Respiratory Tract Infections
There are several restrictive factors, such as medication resistance, recurrency, and inflammation, which will guide researchers to find new effective compounds. This will be an important field in drug development for respiratory infections. Natural compounds are considered to be one of the main sources in new drug development. Historically, numerous plants have been utilized as traditional medicines by people in many nations.4 Many of these plants have been investigated for their antimicrobial and antiviral properties.5–9 With regard to massive variation among natural products, chemical structure diversity causes different antimicrobial potential in natural compounds.10
Besides the antimicrobial activity of the essential oils in natural products, other characteristics such as high vapor pressure, low toxicity, and antiinflammatory potential create a worthwhile theme for using of these natural compounds for new drug development in respiratory infections. Parallel to the roles of the microorganisms in the pathology of respiratory infections diseases, inflammatory process also have a considerable role in the persistence and recurrence of respiratory infectious diseases.
This chapter reviews the antibacterial, antiviral, and antiinflammation effects of essential oils as effective natural compounds. It will also discuss the use of these natural compounds as traditional remedies in treatment of respiratory infections.
2. Traditional remedies in respiratory infections
Traditional medicines utilize natural sources for the treatment of the many diseases.11–13 Historically, infectious diseases have been the major human ailment. Natural sources are used in a variety of forms, including water extracts, tincture or alcoholic extract and incense.14 Based on the historical uses and effective treatments that have been based on many of these traditional remedies, extensive pharmacological research of their antibacterial, antiviral, and antiinflammation activity have been performed.15–17 Abundant information about plants and active compounds in infectious diseases and inflammation related process is available.18–21 Aromatic and fragrant plants are a major part of traditional therapeutic remedies, and they have shown remarkable antibacterial and antiviral activity. Furthermore, many of them also have a significant antiinflammatory activity and are used as adjuvant remedies in the treatment of infection (Table 16.2 and Fig. 16.1). Some of the most active extracts of traditional herbs which have been used as antibacterial and antiviral in the treatment of respiratory infections are summarized in Table 16.3.
Some Famous Traditional Plants That Are Used as Treatment Remedies for Respiratory Diseases
The use of aromatic extracts or burning plants is a common process in traditional medicine. The resultant smoke or fragrance is inhaled to treat respiratory complaints, including cough, cold, infections, and asthma.22,23 Inhalation administration goes back to the ancient cultures and its techniques may be considered as a progressive point in respiratory complaints treatment. The direct effect of such fragrance on the respiratory tract is an advantage of this form of treatment.
Inhalation therapy often involves the aromatic extracts or burning of plant material, and the volatile fraction liberated during the process is inhaled to aid in the healing process. Inhalation of the volatile fraction from aromatic extracts or burning plant matter is a unique method of administration and has been used traditionally to treat respiratory conditions, such as, asthma, bronchitis, and other respiratory infections including the common cold.24 In addition, aerosol delivery of such remedies is well practiced in allopathic medicine and has the advantage of being site specific, thus enhancing the therapeutic ratio for respiratory ailments.25
Table 16.4 and Fig. 16.2 describe several essential oils from Achilla species (Asteraceae family) that have demonstrated appropriate effects on some of the major respiratory infections caused by microorganisms.
Achilla Species Essential Oils, Their Major Chemical Compositions and Their Effects on Some of the Microorganisms That Cause Major Respiratory Infections
Achillea clavennae L.
K. pneumonia, penicillin-susceptible and penicillinresistant S. pneumonia, H. influenza and P. aeruginosa
3. Screening of the antibacterial effects of essential oils
The antimicrobial effects of plants and their extracts have been recognized for a long time. Essential oil is one of the most important and wide spread secondary metabolite in plants and this class of phytochemical compounds and their activities needs attention. These phytochemicals are generally isolated from plant material by distillation methods, such as, hydrodistillation and steam distillation. They contain variable mixtures of several chemical classes, such as terpenoids, specifically monoterpenes and simple phenolic compounds. Some of the higher molecular structures with high molecular weight, such as sesquiterpenes and diterpenes, may be present. A variety of low molecular weight aliphatic hydrocarbons, acids, alcohols, esters or lactones, sulfur-containing compounds and other chemical groups may also be observed. Among the phytochemical compounds, terpenes are responsible for many therapeutic effects in medicinal plants.26–30 Most terpenes are derived from the condensation of isoprene units and are categorized according to the number of these units present in the carbon skeleton. These compounds are responsible for aromaticity and fragrance in many of the plants. The antibacterial activity of volatile oils has been assessed by many researchers.31–34 This potential of essential oils has been used in many pharmaceutical, cosmeceutical, and nutraceutical applications and industrials. There are many differences between the antimicrobial effects of different essential oils. Essential oils and their constituents are an attractive source in new antimicrobial compounds evaluation.35,36
Many of the essential oils have been tested for bactericidal and bacteriostatic effects against a wide range of microorganisms including food spoiling organisms, pathogenic bacteria, yeasts, fungi, and many others. The major differences in antimicrobial activity have been yielded of several distinctive parameters which identify antibacterial characters of the essential oils, some of the major parameters include: (1) bacterial membrane permeability, (2) the hydrophobicity/hydrophilicity of the bacterial membrane, (3) the metabolic characteristics of the microorganism, and (4) their Gram-positive or negative pattern. Although susceptibility of the bacteria to the essential oils is not exactly predictable, many researchers have tried to determine the relationship between the origin of the essential oils and their compounds with their antimicrobial activity. Furthermore, the delivery of medications to the respiratory tract has become an increasingly important method for respiratory disease treatment. The use of inhaler medications has become an invaluable therapeutic in the treatment of different pulmonary disorders, including bronchitis, pneumonia, and others complications.37 Several studies have reported the clinical efficacy of inhalation therapy for the treatment of lung disorders.38,39 Through the effective delivery of medication to the action site, the active compounds are delivered directly into the lungs and this can result in respiratory tract local treatment. This method achieves maximum therapeutic effect, small dose usage, and has fewer side-effect risks compared with those associated with larger doses. Inhalation is a unique treatment with direct effects on respiratory disorder site and is based on the volatility potential of essential oils. Furthermore, there is a need to develop new therapeutic agents for respiratory infections.40–42
Research has been carried out on the wide spectrum of edible plants essential oils to determine the antibacterial potential of their essential oils. The role of these plants as therapeutic agents is remarkable in many cultures. Investigations have reported that thyme and oregano essential oils, based on the phenolic components [such as carvacrol (1) and thymol (2) (Fig. 16.3)] have shown a strong correlation with the inhibition of some of the pathogenic bacterial strains (eg, in Escherichia coli). The correlation between the antibacterial effect of the volatile oils and their chemical compounds, including high amount of the phenolic components such as carvacrol (1) or eugenol (3), has also been confirmed.43 Other essential oils such as oregano, savory, clove, and nutmeg with high concentrations of volatile phenolic compounds inhibit Gram-positive more than Gram-negative pathogenic bacteria.44 However, in some essential oils such as Achillea spp. (Yarrow) strong antibacterial activity was observed against the Gram-negative respiratory pathogens (Haemophilus influenzae, Pseudomonas aeruginosa) while Streptococcus pyogenes was the most resistant to the this oil.45 The other essential oils such as peppermint and spearmint inhibit the methicillin-resistant type of Staphylococcus aureus. Previous reports have clarified that the essential oils containing aldehyde or phenol as a major component represent the highest antibacterial activity. These antibacterial potencies are lower in the essential oils that contain high amounts of terpene alcohols compared to the essential oils containing aldehyde or phenol as a major component.
Other essential oils containing terpene ketone, or ether showed much weaker activity, and oil containing terpene hydrocarbon was relatively inactive. Based on these ﬁndings, essential oils such as thyme, cinnamon, lemongrass, perilla, and peppermint have demonstrated suitable effects on respiratory tract infection.46 The tolerance of Gram-negative bacteria to essential oils has been attributed to the presence of a hydrophilic outer membrane that blocked the penetration of hydrophobic essential oils to the target cell membrane because the Gram-positive bacteria were more exposed to the essential oils than Gram-negative bacteria, which has been reported several times.47–50
Lipids are one of the principal constituents for normal cell membrane function and these compounds supply many operations, such as barrier function in the bacterial cell membrane. The external capsule of some Gram-negative bacteria limits or prevents the penetration of the essential oils into the microbial cell. One of the pronounced examples of the hydrophobicity/hydrophilicity role in bacterial sensitivity to antibacterial compound is H. influenzae. It should be pointed out that the outer membrane of H. influenzae (which forms rough colonies) was more hydrophobic. Hydrophobic antibiotics, such as macrolides, are more active against H. influenzae than E. coli through their shorter oligosaccharide chains than those in E. coli. The effects of the cytoplasmic membrane and/or the embedded enzymes in it have demonstrated lipophilic biocide actions.51 It is generally recognized that the antimicrobial action of essential oils depends on their hydrophilic or lipophilic character. Based on these observations, investigators are trying to indicate the relationship between structural activity of the essential oils compounds and their antibacterial activity.
Certain components of the essential oils can act as uncouplers, which interfere with proton translocation over a membrane vesicle and subsequently interrupt ADP phosphorylation pathways (primary energy metabolism). As a member of the phytochemicals, terpenoids have been observed as a model of lipid soluble agents, which have an impact on the activities of membrane catalyzed enzymes; for example, enzymes involved in respiratory pathways. Particular terpenoids with functional groups, such as phenolic alcohols or aldehydes, also interfere with membrane-integrated or associated enzyme proteins, inhibiting their production or activity. A good deal of antimicrobial compounds which act on the bacterial cytoplasmic membrane cause the loss of 260 nm absorbing material. This causes an increased susceptibility to NaCl, the lysosomes formation and loss of potassium ions, which results in inhibiting respiration and the loss of cytoplasmic material.
Investigations about the cytoplasmic membrane effects of α-pinene (4), β-pinene (5), 1,8-cineole (6), and electron microscopy studies have shown that the essential oils containing these compounds triggered such cytoplasmic material with losing in treated bacterial cells.31,32 The perturbation of the lipid fraction in the plasma membrane causes antimicrobial activity of some of the phytochemicals such as α,β-unsaturated aldehydes and some of monoterpenes. Although these aldehyde compounds can elicit antibacterial effects by acting on membrane functional proteins, such antibacterial effect would be achieved with modifications of membrane permeability and intracellular materials leakage.52–54 The membrane damage leading to whole-cell lysis has been reported by oregano and rosewood essential oils which contains major components as: carvacrol (1), citronellol (7), and geraniol (8).26,55 Phenols such as carvacrol (1), thymol (2), eugenol (3), and other oxygenated aromatic essential oil compounds including phenol ethers [trans-anethole (9), methyl chavicol (10)] and aromatic aldehydes [cinnamaldehyde (11), cuminaldehyde (12)] have been reported to exert both antibacterial and antifungal activity. However, this chemical class—based on the concentration used—are known as either bactericidal or bacteriostatic agents,56 but the phenolic component’s high activity may be further explained in terms of the alkyl substitution into the phenol nucleus, which is known to increase the antimicrobial activity of phenols. The alkylation has been known to change the distribution ratio between the hydrophilic and the hydrophobic phases (including bacterial phases) by the surface tension reduction or the species selectivity mutate based on the bacteria cell wall characters.57 This does not happen with etherified or esterified isomeric molecules, it is possible by describing their relative lack of activity.58 As a member of these compounds carvacrol (1) is one of the few components that has a break apart from effect on the outer membrane of Gram-negative bacteria and causes release of lipopolysaccharide and alters cytoplasmic membrane ions transportation, Similar to carvacrol (1), thymol (2) antimicrobial activity results in structural and functional alterations in the cytoplasmic membrane.59 Interestingly, eugenol (3) and isoeugenol (13) exhibit higher activity against Gram-negative bacteria than Gram-positive bacteria, and when cinnamaldehyde (11) is used against E. coli, its activity is similar to carvacrol (1) and thymol (2) (Fig. 16.3). These compounds alter the membrane, affect the transport of ions and ATP, and change the fatty acid profile of different bacteria.60
Although in some cases alcoholic form shows better potencies compared to acetate form, the presence of an acetate moiety in the structure appeared to increase the activity of the parent compound. In the case of geraniol (8), the geranyl acetate (14) demonstrated an increase in activity against the test microorganisms.48,61,62 A similar effect was also observed in the case of borneol (15), bornyl acetate (16), linalool (17), and linalyl acetate (18) (Fig. 16.3). In addition, the effectiveness of alcoholic compounds very closely depended on the bacterial cell wall, which showed different permeability to alcohol based on chain length.44,63 It has been suggested that an aldehyde group conjugated to a carbon double bond such as citral (19) is an extremely electronegative order, which may explain their activity, and an increase in electronegativity can raise up the antibacterial activity.64 In addition, the under research of aldehydes potency seems to depend not only on the existence of the α,β-double bond but also on the chain length from the renal group and on microorganism tested. It seems that some electronegative compounds, mainly from the cell surface, are responsible for the inhibited growth of the microorganisms, which may interfere in biological processes involving electron transfer and respond with vital nitrogen components and alteration in the operation of membrane-associated proteins. Actually, a greater electronegativity of the molecule would cause a greater encounter of intermolecular hydrogen bond formation with membrane nucleophilic groups and thus a significant irregularity in the lipidic bilayer. Some studies have recommend that carbon tail length also affects the electronegativity of the aldehyde oxygen atom and thus its interaction with the nucleophilic groups of the cell membrane.65 Comparably, the similar antimicrobial activity was detected in the series of the long-chain alcohols which is demonstrated to be resulted from the alkyl chain length.66,67 This structural activity relationship is notable between farnesol (20), nerolidol (21), plaunotol (22), geranylgeraniol (23), phytol (24), geraniol (8), and linalool (17) which act on S. aureus with damages of the cell membranes and losing of K+ ions, while similar mode of actions can be detected by the aminoglycosides such as kanamycin and streptomycin. Farnesol (20) was able to damage cell membranes most effectively than other terpene alcohols. The activities of farnesol (20), nerolidol (21) (sesquiterpenes compounds) on S. aureus were higher than that of plaunotol (22) (diterpene). The effectiveness against S. aureus are in order as follows: farnesol (19) > nerolidol (20)> plaunotol (22) > geranylgeraniol (23), phytol (24) > geraniol (8) and linalool (17) (Fig. 16.3). It has been suggested that maximum activity against S. aureus might depend on the number of carbon atoms in the hydrophobic chain from hydrophilic hydroxyl group, which should be less than 12 but as close to 12 as possible. Neither a shorter nor a longer aliphatic carbon chain, could increase such activity.68,69 The increased effectiveness of sesquiterpenes as enhancers of membrane permeability may stem from their structural resemblance to membrane lipids (eg, linear molecules with internal lipophilic character and a more polar terminus).70 The bacteriostatic potential of the terpenoids was also increased when the carbonyl groups increased in structure.63