May 2017pharmaerudition.org/ContentPaper/2017/may 2017 1-10.pdfInternational Journal of...

May 2017

Vol: 07 Issue: 01(1-10)

International Journal of Pharmaceutical Erudition

www.pharmaerudition.org ,May 2017, 7(1), 1-10 1 | P a g e

ISSN 2249-3875

Review Article

Antimicrobial Drugs of Herbal Origin

Harsh Sargiya*, Pradeep K. Goyal, Bhupendra VyasB. N. Institute of Pharmaceutical Sciences, Udaipur, Rajasthan 313001

Plants produce a diverse array of secondary metabolites, many of which have antimicrobial activity.Someof this compounds are constitutive, existing in healthy plants in their biologically active forms. Others suchas cyanogenic glycosides and glucosinolates, occur as inactive precursors and are activated in response totissue damage or pathogen attack.Keywords: Plants, Antimicrobial activity, Secondary compounds

INTRODUCTIONFinding healing powers in plants is an ancientidea. People on all continents have long appliedpoultices and imbibed infusions of hundreds, ifnot thousands, of indigenous plants, dating backto prehistory. There is evidence thatNeanderthals living 60,000 years ago in present-day Iraq used plants such as hollyhock (12); theseplants are still widely used in ethno medicinearound the world. Historically, therapeutic resultshave been mixed; quite often cures or symptomrelief resulted. Poisonings occurred at a highrate, also. Currently, of the one-quarter to one-half of all pharmaceuticals dispensed in theUnited States having higher-plant origins, veryfew are intended for use as antimicrobials, sincewe have relied on bacterial and fungal sourcesfor these activities. Since the advent of antibioticsin the 1950s, the use of plant derivatives asantimicrobials has been virtually nonexistent.

Clinical microbiologists have two reasons to beinterested in the topic of antimicrobial plantextracts. First, it is very likely that thesephytochemicals will find their way into the arsenalof antimicrobial drugs prescribed by physicians;several are already being tested in humans. It isreported that, on average, two or three antibioticsderived from microorganisms are launched eachyear [2]. After a downturn in that pace in recentdecades, the pace is again quickening asscientists realize that the effective life span ofany antibiotic is limited. Worldwide spending onfinding new antiinfective agents (includingvaccines) is expected to increase 60% from thespending levels in 1993. New sources, especiallyplant sources, are also being investigated.Second, the public is becoming increasinglyaware of problems with the over prescription andmisuse of traditional antibiotics. In addition, manypeople are interested in having more autonomy

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over their medical care. A multitude of plantcompounds (often of unreliable purity) is readilyavailable overthe-counter from herbal suppliersand natural-food stores, and self-medication withthese substances is commonplace. The use ofplant extracts, as well as other alternative formsof medical treatments, is enjoying greatpopularity in the late 1990s. Earlier in thisdecade, approximately one-third of peoplesurveyed in the United States used at least one“unconventional” therapy during the previousyear. It was reported that in 1996, sales ofbotanical medicines increased 37% over 1995. Itis speculated that the American public may bereacting to over prescription of sometimes toxicdrugs, just as their predecessors of the 19thcentury reacted to the overuse of bleeding,purging, and calomel [15].Historic Use of Plants as AntimicrobialsHistorically, plants have provided a source ofinspiration for novel drug compounds, as plantderived medicines have made large contributionsto human health and well-being. Their role is twofold in the development of new drugs: first: theymay become the base for the development of amedicine, a natural blueprint for the developmentof new drugs, or; second: a phytomedicine to beused for the treatment of disease. There arenumerous illustrations of plant derived drugs.Some selected examples, including those

classified as anti-infective, are presented below.The isoquinoline alkaloid emetine obtained fromthe underground part of Cephaelis ipecacuanha,and related species, has been used for manyyears as and amoebicidal drug as well as for thetreatment of abscesses due to the spread ofEscherichia histolytica infections. Anotherimportant drug of plant origin with a long historyof use, is quinine. This alkaloid occurs naturallyin the bark of Cinchona tree. Apart from itscontinued usefulness in the treatment of malaria,it can be also used to relieve nocturnal legcramps. Currently, the widely prescribed drugsare analogs of quinine such as chloroquine.Some strains of malarial parasites have becomeresistant to the quinines, therefore antimalarialdrugs with novel mode of action are required.Similarly, higher plants have made importantcontributions in the areas beyond antiinfectives,such as cancer therapies. Early examplesinclude the antileukaemic alkaloids, vinblatineand vincristine, which were both obtained fromthe Madagascan periwinkle (Catharanthus

roseus syn. Vinca roseus) [9].Present use of plants as antimicrobialIt is estimated that today, plant materials arepresent in, or have provided the models for 50%Western drugs [10]. Many commercially provendrugs used in modern medicine were initiallyused in crude form in traditional or folk healing




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practices, or for other purposes that suggestedpotentially useful biological activity. The primarybenefits of using plant derived medicines are thatthey are relatively safer than syntheticalternatives, offering profound therapeuticbenefits and more affordable treatment.Therapeutic BenefitMuch of the exploration and utilization of naturalproducts as antimicrobials arise from microbialsources. It was the discovery of penicillin that ledto later discoveries of antibiotics such asstreptomycin, aureomycin and chloromycetin[14].Though most of the clinically used antibiotics areproduced by soil microorganisms or fungi, higherplants have also been a source of antibiotics [14].Examples of these are the bacteriostatic andantifugicidal properties of Lichens, the antibioticaction of allinine in Allium sativum (garlic), or theantimicrobial action berberines in goldenseal(Hydrastis canadensis) [14].Economic BenefitWorld wide, there has been a renewed interest innatural products. This interest is a result offactors such as: consumer’s belief that naturalproducts are superior; consumer’s dissatisfactionwith conventional medicines; changes in lawsallowing structure-function claims which results inmore liberal advertising; aging baby boomers;national concerns for health care cost. Thepotential for developing antimicrobials into

medicines appears rewarding, from both theperspective of drug development and theperspective of phytomedicines. The immediatesource of financial benefit from plants basedantimicrobials is from the herbal products market.Major Groups of Antimicrobial CompoundsFrom PlantsOver the centuries man made use of medicinalplants even though he was unable to find arational explanation for their effects. It was notuntil the 19th century and the rapid developmentof organic chemistry and pharmacology, that mandetermined which active principles of group ofprinciples are responsible for a given therapeuticeffect[11]. All plants containing active compoundsare important. The beneficial medicinal effects ofplant materials typically result from thecombinations of secondary products present inthe plant. In plants, these compounds are mostlysecondary metabolites such as alkaloids,steroids, tannins, and phenol compounds, whichare synthesized and deposited in specific parts orin all parts of the plant. These compounds aremore complex and specific and are found incertain taxa such as family, genus and species,but heterogeneity of secondary compounds isfound in wild species . The medicinal actions ofplants are unique to a particular plant species orgroup, consistent with the concept that thecombination of secondary products in a particular




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plant is taxonomically distinct.The plants secondary products may exert theiraction by resembling endogenous metabolites,ligands, hormones, signal transduction moleculesor neurotransmitters and thus have beneficialmedicinal effects on humans due to similarities intheir potential target sites. Therefore, randomscreening of plants for active chemicals is asimportant as the screening of ethnobotanicallytargeted species .Phenolics and Polyphenols Simple phenolsand phenolic acids.Some of the simplest bioactive phytochemicalsconsist of a single substituted phenolic ring.Cinnamic and caffeic acids are commonrepresentatives of a wide group of phenylpropane-derived compounds which are in thehighest oxidation state (Fig. 1).

Fig. 1 Structures of caffeic acidThe common herbs tarragon and thyme bothcontain caffeic acid, which is effective againstviruses, bacteria , and fungi . Catechol andpyrogallol both are hydroxylated phenols, shownto be toxic to microorganisms. Catechol has two2OH groups, and pyrogallol has three. The site(s)and number of hydroxyl groups on the phenolgroup are thought to be related to their relative

toxicity to microorganisms, with evidence thatincreased hydroxylation results in increasedtoxicity . In addition, some authors have foundthat more highly oxidized phenols are moreinhibitory. The mechanisms thought to beresponsible for phenolic toxicity tomicroorganism.Quinones.Quinones are aromatic rings with two ketonesubstitutions (Fig.2). They are ubiquitous innature and are characteristically highly reactive.These compounds, being colored, areresponsible for the browning reaction in cut orinjured fruits and vegetables and are anintermediate in the melanin synthesis pathway inhuman skin.

Fig. 2 Structure of quinoneVitamin K is a complex naphthoquinone. Itsantihemorrhagic activity may be related to itsease of oxidation in body tissues . In addition toproviding a source of stable free radicals,quinones are known to complex irreversibly withnucleophilic amino acids in proteins , oftenleading to inactivation of the protein and loss offunction. For that reason, the potential range ofquinone antimicrobial effects is great. Probable




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targets in the microbial cell are surface-exposedadhesins, cell wall polypeptides, and membrane-bound enzymes. Quinones may also rendersubstrates unavailable to the microorganism. Aswith all plant-derived antimicrobials, the possibletoxic effects of quinones must be thoroughlyexamined. Kazmi et al. [7] described ananthraquinone from Cassia italica, a Pakistanitree, which was bacteriostatic for Bacillus

anthracis, Corynebacterium pseudodiphthericum

, and Pseudomonas aeruginosa and bactericidalfor Pseudomonas pseudomalliae. Hypericin, ananthraquinone from St. John’s wort (Hypericum

perforatum), has received much attention in thepopular press lately as an antidepressant, andDuke reported in 1985 that it had generalantimicrobial properties .Flavones, flavonoids, and flavonolsFlavones are phenolic structures containing onecarbonyl group (as opposed to the two carbonylsin quinones). Flavonoids are also hydroxylatedphenolic substances but occur as a C6-C3 unitlinked to an aromatic ring (Fig.3). Since they areknown to be synthesized by plants in response tomicrobial infection , it should not be surprisingthat they have been found in vitro to be effectiveantimicrobial substances against a wide array ofmicroorganisms. Their activity is probably due totheir ability to complex with extracellular andsoluble proteins and to complex with bacterial

cell walls, as described above for quinones. Morelipophilic flavonoids may also disrupt microbialmembranes . Catechins, the most reduced formof the C3 unit in flavonoid compounds, deservespecial mention. These flavonoids have beenextensively researched due to their occurrence inoolong green teas. It was noticed some time agothat teas exerted antimicrobial activity and thatthey contain a mixture of catechin compounds.These compounds inhibited in vitro Vibrio

cholerae, Streptococcus mutans,, Shigella, andother bacteria and microorganisms. Flavonoidcompounds exhibit inhibitory effects againstmultiple viruses. Numerous studies havedocumented the effectiveness of flavonoids suchas swertifrancheside, glycyrrhizin (from licorice),and chrysin [3] against HIV.

Fig.3 General structures of flavones

TanninsTannin” is a general descriptive name for a groupof polymeric phenolic substances capable oftanning leather or precipitating gelatin fromsolution, a property known as astringency. Theirmolecular weights range from 500 to 3.000 , andthey are found in almost every plant part: bark,wood, leaves, fruits, and roots . They are divided




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into two groups, hydrolyzable and condensedtannins(fig. 4). Hydrolyzable tannins are basedon gallic acid, usually as multiple esters with D-glucose, while the more numerous condensedtannins (often called proanthocyanidins) arederived from flavonoid monomers . Tannins maybe formed by condensations of flavan derivativeswhich have been transported to woody tissues ofplants. Alternatively, tannins may be formed bypolymerization of quinone units [5].

condensed tannin

hydrolyzable tannin

Fig.4 Structure of tanninThis group of compounds has received a greatdeal of attention in recent years, since it wassuggested that the consumption of tannin-

containing bever.Many human physiological activities, such asstimulation of phagocytic cells, host-mediatedtumor activity, and a wide range of anti-infectiveactions, have been assigned to tannins . Thus,their mode of antimicrobial action, as describedin the section on quinones may be related to theirability to inactivate microbial adhesins, enzymes,cell envelope transport proteins, etc. Theantimicrobial significance of this particular activityhas not been explored. Scalbert reviewedthe antimicrobial properties of tannins in 1991.He listed 33 studies which had documented theinhibitory activities of tannins up to that point.According to these studies, tannins can be toxicto filamentous fungi, yeasts, and bacteria.Condensed tannins have been determined tobind cell walls of ruminal bacteria, preventinggrowth and protease activity [6].Coumarins.Coumarins are phenolic substances made offused benzene and a-pyrone rings (Fig.5). Theyare responsible for the characteristic odor of hay.

Fig.5 Structure of coumarinsAs of 1996, at least 1,300 had been identified .

Their fame has come mainly from theirantithrombotic, anti-inflammatory, and




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vasodilatory [8] activities. Several other coumarinshave antimicrobial properties. R. D. Thornes,working at the Boston Lying-In Hospital in 1954,sought an agent to treat vaginal candidiasis in hispregnant patients. Coumarin was found in vitro toinhibit Candida albicans. Its estrogenic effectswere later described . Also, phytoalexins, whichare hydroxylated derivatives of coumarins, areproduced in carrots in response to fungalinfection and can be presumed to have antifungalactivity. General antimicrobial activity wasdocumented in woodruff (Galium odoratum)extracts [13]. All in all, data about specificantibiotic properties of coumarins are scarce,although many reports give reason to believe thatsome utility may reside in these phytochemicals .Further research is warranted.

Terpenoids and Essential OilsThe fragrance of plants is carried in the so calledquinta essentia, or essential oil fraction. Theseoils are secondary metabolites that are highlyenriched in compounds based on an isoprenestructure. They are called terpenes, their generalchemical structure is C10H16, and they occur asditerpenes, triterpenes, and tetraterpenes (C20,C30, and C40), as well as hemiterpenes (C5)and sesquiterpenes (C15). When the compoundscontain additional elements, usually oxygen, theyare termed terpenoids (Fig.6).

Terpenoids are synthesized from acetate units,

and as such they share their origins with fattyacids. They differ from fatty acids in that they

Fig. 6 Structure of mentholcontain extensive branching and are cyclized.

Examples of common terpenoids are methanoland camphor (monoterpenes) and farnesol andartemisin (sesquiterpenoids). Terpenenes orterpenoids are active against bacteria, fungi,viruses , and protozoa . In 1977, it was reportedthat 60% of essential oil derivatives examined todate were inhibitory to fungi while 30% inhibitedbacteria . The ethanol-soluble fraction of purpleprairie clover yields a terpenoid calledpetalostemumol, which showed excellent activityagainst Bacillus subtilis and Staphylococcus

aureus and lesser activity against gram-negativebacteria as well as Candida albicans . Twoditerpenes isolated by Batista et al. [1] were foundto be more democratic; they worked well againstStaphylococcus aureus, V. cholerae, P.

aeruginosa, and Candida spp.Lectins and PolypeptidesPeptides which are inhibitory to microorganismswere first reported in 1942. Recent interest hasbeen focused mostly on studying anti-HIVpeptides and lectins, but the inhibition of bacteria




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and fungi by these macromolecules, such as thatfrom the herbaceous Amaranthus, has long beenknown. Thionins are peptides commonly found inbarley and wheat and consist of 47 amino acidresidues . They are toxic to yeasts and gram-negative and gram-positive bacteria [4]. Fabatin, anewly identified 47- residue peptide from favabeans, appears to be structurally related to g-thionins from grains and inhibits E. coli, P.

aeruginosa, and Enterococcus hirae but notCandida or Saccharomyces.

AlkaloidsAlkaloids rank among the most efficient andtherapeutically significant plant substances. Theyare chemically very diverse group of organicnitrogen compounds(fig.7).

Fig. 7 Structure of an alkaloid (berberine).

Generally they are extremely toxic though theydo have a marked therapeutic effect in minutequantities. For this reason plants containingalkaloids were not often used in folk medicineand then for external application only. Pure,isolated plant alkaloids and their syntheticderivates are used as basic medicinal agents all

over the world for their analgesic, antispasmodic,and bactericidal effects[11].Other CompoundsMany phytochemicals not mentioned above havebeen found to exert antimicrobial properties. Thisreview has attempted to focus on reports ofchemicals which are found in multiple instancesto be active. It should be mentioned, however,that there are reports of antimicrobial propertiesassociated with polyamines (in particularspermidine) , isothiocyanates, thiosulfinates , andglucosides . Polyacetylenes deserve specialmention. Acetylene compounds and flavonoidsfrom plants traditionally used in Brazil fortreatment of malaria fever and liver disordershave also been associated with antimalarialactivity.

Much has been written about the antimicrobialeffects of cranberry juice. Historically, womenhave been told to drink he juice in order toprevent and even cure urinary tract infections. Inthe early 1990s, researchers found that themonosaccharide fructose present in cranberryand blueberry juices competitively inhibited theadsorption of pathogenic E. coli to urinary tractepithelial cells, acting as an analogue formannose. Clinical studies have borne out theprotective effects of cranberry juice . Many fruitscontain fructose, however, and researchers arenow seeking a second active compound from




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cranberry juice which contributes to theantimicrobial properties of this juice [16].

CONCLUSIONScientists from divergent fields are investigatingplants anew with an eye to their antimicrobialusefulness. A sense of urgency accompanies thesearch as the pace of species extinctioncontinues. Laboratories of the world have foundliterally thousands of phytochemicals which haveinhibitory effects on all types of microorganismsin vitro. More of these compounds should besubjected to animal and human studies todetermine their effectiveness in whole-organismsystems, including in particular toxicity studies aswell as an examination of their effects onbeneficial normal microbiota. It would beadvantageous to standardize methods ofextraction and in vitro testing so that the searchcould be more systematic and interpretation ofresults would be facilitated. Also, alternativemechanisms of infection prevention andtreatment should be included in initial activityscreenings. Disruption of adhesion is oneexample of an anti-infection activity notcommonly screened for currently. Attention tothese issues could usher in a badly needed newera of chemotherapeutic treatment of infection byusing plant-derived principles.

REFERENCES1. Batista, O., A. Duarte, J. Nascimento, and M.F. Simones. 1994. J. Nat. Prod. 57: 858–59.2. Clark, A. M. 1996. Pharm. Res. 13:1996.3. Critchfield, J. W., S. T. Butera, and T. M.Folks. 1996. AIDS Res. Hum. Retroviruses

12:39.4. Fernandes de Caleya, R., B. Gonzalez-Pascual, F. Garcia-Olmedo, and P. Carbonero.1972. Appl. Microbiol. 23:998–1000.5. Geissman, T. A. 1963. Flavonoid compounds,

tannins, lignins and related compounds, Elsevier,New York.6. Jones, G. A., T. A. McAllister, A. D. Muir, andK. J. Cheng. 1994. Appl. Environ. Microbiol.60:1374–1375.7. Kazmi, M. H., A. Malik, S. Hameed, N. Akhtar,and S. Noor Ali. 1994. Phytochemistry 36:761–763.8. Namba, T., O. Morita, S.-L. Huang, K.Goshima, M. Hattori, and N. Kakiuchi. 1988.Planta Med. 54:2779. Nelson, R. 1982. Med. Pediatr. Oncol. 10:115–117.10. Robbers, J., M. Speedie, and V. Tyler. 1996.Pharmacognosy and pharmacobiotechnology.Williams and Wilkins, Baltimore.11. Stary, F. 1996, The natural guide to medicinal

herbs and plants, Barnes&Noble Inc.,




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12. Stockwell, C. 1988. Nature’s pharmacy.Century Hutchinson Ltd., London, UnitedKingdom.13. Thomson, W. A. R. (ed.). 1978. Medicines

from the Earth. McGraw-Hill Book Co.,Maidenhead, United Kingdom.14. Trease, G. and Evans, W. 1972.

Pharmacognosy, Univ. Press, Aberdeen, GreatBritain.15. Yankauer, A. 1997. Perspect. Biol. Med.41:132–133.16. Zafriri, D., I. Ofek, R. Adar, M. Pocino, and N.Sharon. 1989. Inhibitory. Antimicrob. Agents

Chemother. 33:92.

Source of Support: Nil, Conflict of Interest: None


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