Plant Natural Products as a Potential Source for ...

Anti-Infective Agents in Medicinal Chemistry, 2009, 8, 000-000

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Plant Natural Products as a Potential Source for Antibacterial Agents: Recent Trends M. Shahid1,*,#, A. Shahzad2, F. Sobia1, A. Sahai2, T. Tripathi3, A. Singh1, H.M. Khan1 and Umesh4 1

Department of Medical Microbiology, JN Medical College & Hospital, Aligarh Muslim University, Aligarh-202002, Uttar Pradesh, India; 2Plant Biotechnology Unit, Department of Botany, Aligarh Muslim University, Aligarh-202002, Uttar Pradesh, India; 3 Department of Biochemistry, JN Medical College & Hospital, Aligarh Muslim University, Aligarh-202002, Uttar Pradesh, India; 4Department of Microbiology, Uttrakhand Forest Hospital Trust Medical College, Haldwani-263139, Uttrakhand, India Abstract: Pasteur and Joubert, in 1877, were among the first to recognize the potential of microbial products as therapeutic agents and demonstrated that common microorganisms could inhibit the growth of Anthrax bacilli. However, the milestone in the field of antimicrobial agents was the advent of penicillin, in 1928, by Alexander Fleming from a strain of the mold Penicillium. Since then, the fungi and higher plants have been searched for the production/preparation of novel antibacterial compounds, including cephalosporins and aminoglycosides. However, due to increasing usage and selection pressure, bacteria have started expressing resistance to these compounds. Hence, there is an urgent need to review and search for newer antibacterial compounds derived from plant species. In this review, the potential of plant species to yield newer antibacterial agents will be illustrated with an emphasis on compounds exclusively isolated in very recent years. Some of the issues pertinent to this area will be briefly reviewed and it is hoped that this would definitely stimulate further discussions and research on this important aspect.

Keywords: Plant-derived, antibacterial, recent compounds, antimicrobial resistance. #

Author Profile: M. Shahid is presently serving as Associate Professor & Consultant Microbiologist in the Department of Microbiology of J.N. Medical College & Hospital, Aligarh Muslim University, India, and also the In charge of Section of Antimicrobial Resistance Researches and Molecular Biology of the same department. He has recently been awarded Young Scientist Award by Department of Science & Technology, Ministry of Science & Technology, Govt. of India and financial assistance to explore the antibiotics resistance problems and reservoirs of the resistance genes in Indian bacterial population. He was also been awarded Commonwealth Academic Fellowship by British Council and Association of the Commonwealth Universities, U.K., during 2005-2006 analyzing similar type of antibiotics resistance problem on which he worked as Honorary Research Fellow in the Section of Immunity & Infection, The Medical School, University of Birmingham, U.K. and Heartlands NHS Hospital, Birmingham, U.K. His Field of Interest and Research is confined to Mechanism and Resistance to beta-lactam antibiotics with special interest in CTX-M and AmpC
-lactamases, Plasmid mediated drug resistance, Indigenous drugs and Antimicrobial activities of extracts from endangered medicinal plants, and Hospital Infection Control policies. He is presently the member of numerous scientific bodies, both international and national, including “Infectious Diseases Society of America” and “International Society for Infectious Diseases”. He was also been awarded many awards including British Council Travel Award (2005-2006) to present his scientific achievements in various International Scientific meetings. He has many books, book chapters, and scientific papers in journals of high repute to his credit. He has also been the member of the reviewer panel and Editorial Board of various International Journals/publication houses including those of Bentham Science Publications, USA, and Global Science Books, UK. INTRODUCTION The antibiotic era began in the early part of the last century, with introduction into widespread civilian use of the first powerful antibiotic penicillin, followed by many other classes of such ‘wonder drugs’. Over-usage and even appropriate usage over the past 50 years has led to antibiotic resis-

*Author correspondence to this author at the Associate Professor & Consultant, Department of Microbiology, JN Medical College & Hospital, Aligarh Muslim University, Aligarh-202 002, U.P., India; Tel: +91-5712720382; Mobile: 009411802536; Fax: +91-571- 2720382; E-mails: [email protected]; [email protected]

1871-5214/09 $55.00+.00

tance, where antibiotics once effective are rendered inactive against their bacterial cellular targets. There are two important cellular targets of antibacterial antibiotics and in general terms include: i) Peptidoglycan of the cell wall with no equivalent in the mammalian cells ii) Bacterial ribosomes which differ in size and composition compared to the mammalian ribosomes Peptidoglycan provides mechanical strength to the bacterial wall while damage to peptidoglycan results in osmotic lysis of the cell. To allow cell growth, peptidoglycan must be continuously remodeled, i.e. bonds between peptidoglycan © 2009 Bentham Science Publishers Ltd.

2 Anti-Infective Agents in Medicinal Chemistry, 2009, Vol. 8, No. 3

chains must be broken and new chains inserted. Bacteria have numerous enzymes, which can synthesize crosslinks and remodel peptidoglycan. These enzymes are the target of cell wall inhibitors such as penicillins and cephalosporins and other molecules possessing a
-lactam ring. As peptidoglycan is totally lacking in mammalian cells, peptidoglycan inhibitors have high selective toxicity towards bacterial cells, some of the best are currently in use as antibiotics. In general, they act specifically on growing bacterial cells that are forming and crosslinking peptidoglycan. Ribosomal inhibitors are subdivided into two classes based on their mechanism of action, i) bacteriocides (eg. aminoglycosides), ii) bacteriostatins (represented by tetracycline, oxazolidinones, macrolides, etc). These agents cause inaccurate translation of mRNA into proteins and incorporation of error containing proteins into the bacterial envelope, reducing its integrity. There are other antibiotics that inhibit bacterial enzymes, such as the folic-acid like metabolism inhibitor trimethoprim and its combination with sulfanilamide. Folic acid is an essential cofactor for many enzymes that transfer one carbon unit in biosynthetic reactions. Sulfanilamide and related drugs are structural analogues of para-amino benzoic acid (PABA), the precursor of folic acid, and inhibits its synthesis. The antibiotic action of sulfanilamide can be reversed by the end-products of metabolic pathways blocked by folate deprivation and include purines, pyrimidines, some amino acids or by folic acid itself. These biosynthetic reactions require folic acid in its fully reduced form tetrahydrofolic acid (THFA). In the reaction which converts dUMP to dTMP, THFA is oxidized to dihydrofolic acid (DHFA), which is metabolically inactive and must be reduced back to THFA by dihydrofolate reductase. DHFA reductase is inhibited by trimethoprim. Sulfanilamides block THFA synthesis while trimethoprim prevents reduction of DHFA. Ethnobotany of Antibiotics The increased prevalence of antibiotic resistance is an outcome of evolution. Any population of organisms, bacteria included, naturally includes variants with unusual traits such as the ability to withstand an antibiotic attack by a natural product. When a person takes an antibiotic or natural product with activity, the compound inhibits the proliferation or drug kills the bacterium, leaving behind or ‘selecting’ those that can resist it. These fit bacteria then multiply, becoming the predominant microorganism, with deleterious traits to mannow becoming antibiotic resistant. The antibiotic does not technically cause the resistance but induces it to happen by creating a situation where an already existing strain variant can flourish whenever antibiotics are used; thus occurs selective pressure for resistance to an antibiotic or natural product. Incidents of epidemics due to drug resistant microbes pose enormous public health concerns. The overriding principle of medicine is ‘do not harm’ yet in the case of antibiotics, harm is inevitable, for use, even appropriate usage, may select for resistance. Plant based antimicrobials represent a vast untapped source for medicine and has enormous therapeutic potential, as they are effective on treatment of infectious diseases while

Shahid et al.

simultaneously mitigating many of the side effects that are often associated with synthetic antimicrobials. Phytomedicines usually have multiple effects on the body, for example, Hydrastis extracts not only have antimicrobial activity, but also increases blood supply to the spleen promoting optimal activity of the spleen to release mediating compound [1]. Hence, they are effective yet possess multiple cellular targets. The first generation of plant drugs were simply botanicals employed in more or less their crude form. Several such effective medicines include cinchona, opium, belladonna and aloe which were selected as therapeutic agents based on empirical evidence of their clinical application by traditional societies from different parts of world. Second generation plant drugs were based on scientific processing of the plant extract to isolate their active constituents. These phytopharmaceutical agents were pure molecules and some compounds were even more pharmacologically active than their synthetic counterparts (e.g. quinine from Cinchona, reserpine from Rauvolfia, taxol from Taxus species) see Figs. (1a-1c ) respectively. These compounds differed from synthetic therapeutic agents only in their origin and they followed same method of development and evaluation as other pharmaceutical agents. Development of third generation phytotherapeutic agents a top-bottom approach is usually adopted. This consists of first conducting a clinical evaluation of the treatment modalities and therapy as administered by traditional doctors or as used by the community as folk medicine. This evaluation has followed by acute and chronic toxicity studies in animals in addition to studies on cytotoxicity. It is only if the substance has an acceptable safety index would it be necessary to conduct detailed pharmacological/biochemical studies. Historically, plants provided various anti-infective agents as natural products, and where they first reported as antibacterial agents, providing the alkaloids quinine, emetine, and berberine [see Figs. (1a, 1d, 1e) respectively]. Plants containing protoberberines and related alkaloids, picralima-type indole alkaloids and garcinia biflavonones, are also used in traditional medicine in Africa, and have been found to be active against wide variety of microorganisms. The isoquinoline alkaloid emetine obtained from the underground root of Cephaelis ipecacuanha, has been used an amoebicide as well as in the treatment of abscesses due to E. histolytica infections. Another related alkaloid and drug quinine Fig. (1a), is useful in treatment of malaria, and can be also used to relieve nocturnal leg cramps. Antileukaemic alkaloids, vinblastine Fig. (1f) and vincristine Fig. (1g), both obtained from Catharanthus roseus, and the anticancer agents taxol Fig. (1c), homoharringtonine and several derivatives of camptothein are also plant natural products. A well-known benzylisoquinoline alkaloid, papaverine [Fig. (1h)] has been shown to have a potent inhibitory effect on the replication of several viruses including cytomegalovirus, measles and HIV [2]. Three new atropisomeric naphthylisoquinoline alkaloid dimers, michellamines A, B and C were recently isolated from Ancistrocladus korupensis [see Fig. (1i)], and showed potential anti-HIV activity with michellamine B being most potent. These compounds were capable of complete inhibit-

Plant Natural Products as a Potential Source for Antibacterial Agents

Anti-Infective Agents in Medicinal Chemistry, 2009, Vol. 8, No. 3

MeO

H

N H

HO

O

O

O

O

O

MeO

H

O

H H

N

HO H 3C

O

O OH O O

N H

O

OH

O

O

NH

OMe

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3

O

OMe OMe

N

OMe

(a)

(b)

(c)

OH N

O

N H

O

O

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O

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H

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OH

O

HN

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N

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O

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+

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(d)

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O

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(e)

(f)

OH

OH

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HN O

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OH

O

OH

OCH3

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N

OH O

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H O

OCH3

H H O

OCH3 OH

O

HO CH3O

O

(g)

CH3O

N

NH

(h)

OH

(i)

Fig. (1). Important antibacterial alkaloids reported from medicinal plants.

tion of the cytopathic effects of HIV-1 and HIV-2 on human lymphoblastoid target cells in vitro [3]. From the last century, a scientific interest for phytotherapy increased in the fields of immunology, oncology, and hematology [4]. Concurrently, phenolic compounds have been studied extensively in these fields, and are molecules that have played several roles in plant physiological processes, as protection from UV, defense against pathogens, pollination and dissemination, symbiosis and allelopathic interactions [5]. Intake of phenolic compounds as antioxidants prevents numerous chronic diseases related to cardiovascular disease, cancer, diabetes, and bacterial and parasitic infections [6, 7].

In bacteriology plants whose extracts recently reported to have antibacterial activity are discussed below. Stemona tuberosa Stemona species (Stemonaceae) is used in Chinese traditional medicine as an insecticidal and antitussive agent [8] and the root extracts of these plants are used for respiratory disorders, including pulmonary tuberculosis and bronchitis. Extracts are also effective against certain insects and agricultural pests [9, 10]. Pharmacological studies showed that ethanol extracts of S. tuberosa inhibit growth of bacteria and fungi [11]. Yang et al. [12] isolated several stilbenoids from the roots of S. sessilifolia, which showed antibacterial activ-

4 Anti-Infective Agents in Medicinal Chemistry, 2009, Vol. 8, No. 3

ity against S. aureus and S. epidermidis. Lin et al. [13] investigated dichloromethane fractions from roots of S. tuberosa and found 13 new stilbene derivatives now designated stilbostemins N-Y (compounds 1-12) [see Fig. (2)] and stemanthraquinone (compound 13). A series of dihydrostilbenes (compounds 14-18) were previously described by Pacher et al., [14] and Yang et al. [12] and are shown in Fig. (2). Stilbenoides were the main non-alkaloid constituents from S. tuberosa. It was reported that the aromatic C-methylation of stilbenoids was a typical chemical feature of Stemona genus [14, 15] and this feature was observed in stilbenoids present in root extracts of S. tuberosa except compound 1 Fig. (2a) and compound 4 Fig. (2c). A peculiar feature found in S. tuberosa is the natural occurrence of 2,6-dimethyl substituted dihydrostilbenes, a molecular oddity which are rarely found in plant kingdom. Stilbostemin O (compound 2) Fig. (2b) was described as 3,5-dihydroxy-4’-methoxy-4-methylbibenzyl and stilbostemin P (compound 3) Fig. (2b) was designated as 3,5dihydroxy-2’,4’-dimethoxy-4-methyl bibenzyl. Stilbostemin Q (compound 4) was obtained as a yellow amorphous powder with molecular formula C16H18O4 and its chemical structure was described as 3,5-dihydroxy-2’,4’-dimethoxyl bibenzyl. Stilbostemin R (compound 5) Fig. (2d) was determined as 3,5-dihydroxy-2’-methyl bibenzyl, while stilbostemin S (compound 6) Fig. (2d) and stilbostemin T (compound 7) Fig. (2d) were obtained as yellow amorphous powders and their molecular formulae were established as C17H20O4 respectively. The substitution pattern of the dimethoxy benzyl fragment of compound 6 was similar to that of 3, while that of 7 was similar to the ring B in stilbostemin K [12]. Stilbostemin U (compound 8) Fig. (2e) and stilbostemin V (compound 9) Fig. (2e) were colorless oils with molecular formula C10H22O4; the chemical structure of compound 8 was identified as 3- hydroxy-5, 2’, 4’-trimethoxy-2 methyl bibenzyl. The molecular formula of stilbostemin W (compound 10) Fig. (2f) was established as C17H20O3. Stilbostemin X (compound 11) Fig. (2f) and stilbostemin Y (compound 12) Fig. (2f) were isolated as light yellow oil and a yellow amorphous powder, respectively, and have same molecular formula C18H22O4. Structure of compound 11 was determined as 3,5-dihydroxy-2’,4’-dimethoxy-2,6-dimethyl bibenzyl and that of compound 12 as 3,5-dihydroxy-2’,5’dimethoxy-2,6-dimethyl bibenzyl. Stemanthraquinone (compound 13) Fig. (2i) was obtained as an orange amorphous solid with the molecular formula C16H14O4. By comparing spectroscopic data with those of ephemeranthoquinone [16], it was proposed that compound 13 should be a derivative of 1’’,2’’-dihydrophenanthrene-2’,5’-quinone and its structure was established as 3-hydroxy-4’-methoxy-4-methyl-1’’,2’’dihydrophenanthrene-2’,5’-quinone. All these new compounds were assayed for antibacterial activity against Staphylococcus aureus (ATCC 25923), Bacillus pumilus (ATCC 21356), B. subtilis, Klebsiella pneumoniae (ATCC 13883), and fungi Candida albicans and Cryptococcus neoformans. Among the tested compounds, compound 8 displayed good antibacterial potential against B. pumilis at MIC 12.5-25 μg/mL while, compounds 8, 11 and 12 showed marginal antifungal activity against C. neoformans with MICs at 50 μg/mL.

Shahid et al. H3CO H3CO

6

5 4

2" 1

A

HO

3

HO

B

1'

R2

4'

H 3C

5'

6'

1"

2

R1

3'

2'

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Compound 1 (a)

R1 H OCH3 H OCH3 (b)

Compound 2 Compound 3 Compound 14 Compound 15

R2 OCH3 OCH3 H H

H3CO

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HO

HO

R1

R1

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HO

Compound 4 R1 = OCH3 Compound 16 R1 = H (e)

CH3

Compound 5 Compound 6 Compound 7

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R1 H OCH3 H (d)

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OH

CH3

R1

R1

R2 HO

R2 HO

CH3

R1 Compound 8. OCH 3 Compound 9. H

R2 H OCH3

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CH3

R1 Compound 10. H Compound 11. OCH3 Compound 12. H (f)

(e)

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OH

H3CO

HO

R2 H H OCH3

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OH

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CH3

HO

(g)

(h) 2"

1"

2'

2

OH

3

O 3'

4

5'

H 3C

O

4'

OCH3

(i)

Fig. (2). Stilbenoids from the roots of Stemona tuberose.

Caesalpinia benthamiana Caesalpinia benthamiana is a shrub of the family Caesalpinaceae and is commonly found in the secondary forest biome in Ghana, Africa. It is used in traditional medicine for the treatment of topical infections and wounds [17]. A paste made from powdered root bark mixed with shea butter, palm

Plant Natural Products as a Potential Source for Antibacterial Agents

oil or palm kennel oil is reported to be used topically. Microbial infections and the presence of oxygen-free radicals are considered as common impediments to wound healing, hence any agent capable of eliminating or reducing the number of microbes present in wounds as well as reducing the levels of reactive oxygen species may facilitate the process of wound healing [19]. Previous studies on the leaves of C. benthamiana reported the isolation of gallic acid and its derivatives possessing antibacterial properties [20]. Piccatannol, trans-resveratrol, apigenin and scirpusin A have been isolated from a related species Mezoneuron cucullatum [21]. A variety of cassane diterpinoids have been isolated from Caesalpinia species [22]. Dickson et al. [18] isolated two new cassane diterpenoids and designated them as benthamin 1 and 2. A third compound isolated from this species was a deoxy form of caesaldekarin C which is also referred as methyl vouacapenate and was previously isolated from Caesalpinia major, C. bonducella, Vouacapoua americana and V. macropetala. In these latter species this compound was isolated together with -sitosterol and stigmasterone. Compound 1 Fig. (3a) was established as deoxycaesaldekarin C with a molecular formula C21H31O3 [21] while compounds 2 and 3 were designated as benthamin 1 and benthamin 2, respectively. Benthamin 1 was isolated as white crystals from CH2 Cl2 fraction and had a molecular formula C21H26O3. Its systemic name was designated as 4,7, 11b-trimethyl-1,2,3,4,4a,5,6,11b-octahydro-10-oxa-cyclo-pen (b) phenanthrene-4-carboxylic acid methyl ester] Fig. (3b) and was proposed that its structure is an aromatized form of deoxycaesaldekrin C. The systemic name of benthamin 2 was designated as 4,11b-dimethyl-7-methylen-1,2,3,4,4a,5, 6,6a, 7,11,11a,11b-dodecahydro-10-oxa-cyclopental (b) phenanthrene-4- carboxylic acid methyl ester Fig. (3c) and was also obtained as white crystals from dichloromethane (CH2Cl2) fraction with a molecular formula C21H28O3.

Anti-Infective Agents in Medicinal Chemistry, 2009, Vol. 8, No. 3

flavus (NCTC 7743) followed by compound 3. Compounds 1 and 3 also showed free radical scavenging and antioxidant activities with compound 3 being the more active compound having IC50 values in the DPPH (2, 2-diphenyl-1picrylhydrazyl) method as described by Brand Williams et al. [23] and TBA (thiobarbituric acid) lipid peroxidation assays of 42.7 and 74.2
M, respectively. It was suggested that the relatively stronger antioxidant activity of benthamin 2 appeared to be associated with the presence of exocyclic methylene functional group at C-17. Deoxycaesaldekarin C was also found to possess both antibacterial and antioxidant activities with the presence of methyl ester and methyl functional groups, as well as unsaturated furan ring, conferring antibacterial activity. Jatropha podagrica Jatropha (Euphorbiaceae) is a shrub commonly found in Africa, Asia and Latin America. Traditional uses of Jatropha include skin infections, sexually transmitted diseases, jaundice and fever [24]. This plant was also found to possess anti-tumor and insecticidal activities [25, 26]. Previous studies on Jatropha reported isolation of several types of diterpenoids from the roots of these plants [27, 28]. Aiyelaagbe et al. [29] isolated new diterpenoids Fig. (4a, 4b) along with four known diterpenoids Fig. (4c-4f). Hexane, chloroform and methanol extracts were investigated against Grampositive bacteria, and the hexane extract was found to be most active. Compound 1 was named japodagrin and is chemically described as 1, 2 epoxy-15-epi-4E-jatrogrossidentadion and its structure composed of a lathyrane ring system, which is common in Euphorbiaceace plants. Japodagrin is the first compound discovered to have a trisubsituted epoxide at positions C1 and C2. Compound 2 was named as japodagrone and has a jatrophane skeleton which is generally found in jatrophone [30], suggesting that this compound was not a lathyrane diterpenoid.

16

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14

8

13

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13

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9

10

12

1

7

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2

13 4

10

O HO

18

(c)

Fig. (3). Cassane diterpenoids obtained from Caesalpinia benthamiana.

Bioactivity of all three compounds was determined and all were found to possess antibacterial as well as antioxidant activities, with compound 2 being the most active with MICs of 47.0
M against S. aureus (NCTC 4163) and Micrococcus

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Fig. (4). Diterpenoids obtained from Jatropha podagrica.

18

6 Anti-Infective Agents in Medicinal Chemistry, 2009, Vol. 8, No. 3

Four other diterpinoids, 4Z- jatrogrossidentadion (compound 3), 15-epi-4Z-jatrogrossidentadion (compound 4), 2 hydroxyisojatrogrossidion (compound 5) and 2-epihydroxyisojatrogrossidion (compound 6) were also. These compounds were originally isolated from the roots of Jatropha grossidentata and have also been found in J. weddelina [31, 32]. Antimicrobial activity of these compounds was assessed by Aiyelaegbe et al. [26] and compound 1 was found to be active against B. subtilis (ATCC 6051) and S. aureus (ATCC 25923), providing inhibitory zones of 16 and 12 mm, respectively, at a concentration of 20 μg/disc. Compound 2 showed activity only against B. subtilis (ATCC 6051) giving a zone of 12 mm at 20 μg/disc, while compounds 3-6 displayed activity against B. subtilis with zone of inhibitions of 20, 17, 31 and 35 mm, respectively, as well as against S. aureus with zones of 10, 9, 21 and 26 mm, respectively. All of these compounds were found inactive against E. coli (ATCC 25922) and P. aeruginosa (ATCC 27853).

Shahid et al.

with a MIC of 15.6 μg/mL and a minimum bactericidal concentration (MBC) of 125 μg/mL. The same compound also showed antimicrobial activity against other Gram-positive bacteria including Streptococcus pyogenes and Streptococcus pneumoniae while no activity was observed against Gramnegative bacteria (P. aeruginosa, E. coli, S. typhimurium). 20 1

3

10

H

11

E. serrulata is a shrub growing 1-2.5 m tall, has hairy leaves, often obscured by the resin covering the leaf surface [41]. A previous chemical investigation of this plant [42] led to the isolation of 8, 16-dihydroxyserrulat-14-en-19-oic acid which is a typical example of the most common class of diterpinoids in Eremophila spp.-the serrulatanes Fig. (5a) [42, 43]. A study by Ghisalberti, in 1992, led to isolation of a dimethoxy derivative of a tricyclic diterpene phenolic acid which contains 3-epi-pseudopterosin skeleton [44]. Ndi et al. [40] isolated antimicrobial compounds from leaves of E. serrulata, naming two major constituents napthaquinone and 9-methyl-3-(4-methyl-3-pentenyl)-2, 3-dihydronaphtho[1,8bc]pyran-7,8-dione Fig. (5b). Naphthopyran 2 is structurally similar to biflorin, a diterpene quinone which was first isolated from Capraria bifloria (Scrophulariaceae) [45, 46]. Biflorin was the first O-naphtho (1, 8-bc) pyran quinoid found in nature which, showing antimicrobial properties against Gram-positive organisms. Compound 2 also showed structural similarities to the mansonones, which are sesquiterpenoid quinones with potent activity against MRSA [47-49], and to a serrulatane-type diterpenoid, 20-acetoxy-8hydroxyserrulat-14-en-19-oic acid Fig. (5c). The known serrulatane-type diterpenoids [8, 20 dihydroxyserrulat-14-en-19 oic acid Fig. (5d) and 8, 20 diacetoxyserrulat-14-en-19 oic acid Fig. (5e)] also possess antimicrobial activity. Compounds 2-5 showed antimicrobial activity against S. aureus (ATCC 29213) with MICs ranging from 15.6-250 μg/mL and compound 2 was reported as most active agent

12 14

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Eremophila serrulata Eremophila (Myoporaceae) is native only to Australia and includes about 200 different species [33]. This plant has recorded medicinal uses in traditional Aboriginal cultures for skin sores and sore throat medication [34, 35]. Pharmacological activities of preparation of E. duttoni and E. alternifolia activity includes antibacterial activity against Grampositive bacteria [36, 37 while others have demonstrated antimicrobial activity against Gram-positive bacteria including multidrug-resistant S. aureus (MRSA) [38]. Previous phytochemical studies on Eremophila species have reported the isolation of several diterpenoids [Ghisalberti, 42] from resin extractable with organic solvents [39, 40].

9a

3a 10

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6

9

OH

COOH

H

H

H

(c)

(d) O 22

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24

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H H

(e)

Fig. (5). Antimicrobial compounds from Eremophila serrulata.

Uraria picta Uraria picta (Syn. Doodia picta) belongs to Papilionaceae and is distributed throughout Bangladesh, India, Sri Lanka, Tropical Africa, Malay Islands and the Philippines [50, 51]. It is a sparingly branched suffructicose perennial herb, with a height of 0.9-1.8m. Traditionally this plant is used as an antidote to venom of Echis carinata, which is a dangerous Indian snake [50], while its leaves are used as antiseptic and to cure gonorrhea. Fruits and pods of the same plant have been found to use against cough, chills and fever [50, 51]. U. lagopoides has been reported for its analgesic and anti-inflammatory activities [52] while extracts of U. critina have demonstrated nitric oxide-scavenging and antioxidant effects [53]. Rahman et al. [50] also described two new isoflavanoids (compounds 2 and 4) Fig. (6a, 6b) along with 6 known compounds, including isoflavanones, titerpenes and steroids, and several were found to possess antibacterial and antifungal properties.

Plant Natural Products as a Potential Source for Antibacterial Agents 8

HO

O

9

7 10

5

6'

1'

5'

4

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2'

4'

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3'

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OH 5"

10"

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2 and 4, were found to be most active against S. aureus with a MICs of 12.5
g/mL; 0.038
mol and 12.5
g/mL; 0.025
mol, respectively, whereas 6-prenyl-isoflavanone (compound 6) showed highest activity against E. coli (MIC = 12.5
g/mL ; 0.035
mol ) and C. albicans ( MIC = 12.5
g/mL; 0.035
mol ).

2 3

6

Anti-Infective Agents in Medicinal Chemistry, 2009, Vol. 8, No. 3

5' 4'

2'

OH

3'

OMe

(b)

Fig. (6). Isoflavonones isolated from Uraria picta.

Flavonoids and isoflavonoids exhibit anti-inflammatory, antithrombotic, antiviral and hepatoprotective activities, purportedly due to their free radical scavenging potential [54]. Genistein and 2’ hydroxygenistein were reported potent inhibitors of indole-3-acetic acid oxidase activity [55] although they possess cellular cytotoxicity. Numerous isoflavones cause strong lipid peroxidation inhibitory effects [56] and numerous prenylated isoflavonones were also reported to have antimicrobial activity [57]. Vacuum Liquid Chromatography (VLC) fractionation of CHCl3 extract of root bark of U. picta provided isolation of titerpene (compound 1) and isoflavanoides (compounds 2-5). Compound 1 was identified as 12-oleanene 3, 22-diol [58] and was reported for the first time from genus Uraria. Compound 2 was obtained as a yellow waxy amorphous solid with a molecular formula C17H14O7, and was chemically identified as 5, 7-dihydroxy-2’-methoxy-3’, 4’-methylenedioxy isoflavanone. Compound 3 was previously reported from Poecilanthe parviflora [59] and was first isolated from C. uraria by Rahman et al. [53] This compound, with a molecular formula C17H16O7, was identified as 5, 7, 4’trihydroxy-2’, 3’-dimethoxyisoflavanone and is now known as parvisoflavanone. However, compound 4 was reported as a new isoflavanone isolated as yellow gum with a molecular formula C26H20O10. It was chemically identified as 4’, 5dihydroxy-2’, 3’-dimethoxy-7-(5-hydroxy oxychromen-7yl)isoflavanone. Compound 5 was identified as 4’, 5, 7trihydroxy-2’- methoxy isoflavanone (isoferreirin) [60], while compound 6 and compound 7 were identified as 2’, 4’, 5, 7-tetrahydroxy-6-(3-methyl-but-2-enyl) isoflavonone [61] and 2’, 4’, 5’ 7-tetrahydroxyisoflavanone [61, 62], respectively. Although isoflavonones 5-7 were previously reported in legumes [60, 61] they were first isolated from genus Uraria [64]. The MICs of the compounds 1-7 ranged between from 12.5-200
g/mL against S. aureus (NCTC 10788), B. subtilis (NCTC 8236), E. coli (NCTC 9001) and P. vulgaris (NCTC 4175), Aspergillus niger (NCPF 3149) and C. albicans (IMI 149007). Titeropene (compound 1) showed highest activity against P. vulgaris, with a MIC of 12.5
g/mL. Isoflavanones

Santolina corsica Jordan et Fourr Genus Santolina is widely distributed in Mediterranean region, but S. corsica Jordan et Fourr is an endemic species to Corsica and Sardinia [65]. It is a shrub of 30-50 cm height which preferably grows in rocky and sunny places and bears persistent leaves and yellow colored flowers. The composition of essential oils from other species of Santolina, such as S. chamaecyparissus, S. oblongifolia and S. canescens, has previously been investigated, and all of them are found to produce monoterpene-rich oils and with chemically diverse compositions. A solvent extract from roots of S. corsica was found to contain sesquiterpenes, hydrocarbons, titerpenes, furylthienylbutenynes and a spiroketalenol [66]. The chemical composition of essential oil of the S. corsica, from a Sardinian sample, possessed mainly camphor (18.5%), artemisia ketone (12.9%) and borneol (7.4%) [67], while Cosican botanical sample contained artemisia ketone (20.0%), phellandrene (14.4%), myrcene (11.7%) and Santolina triene (8.2%) as the dominant components [68]. Besides the main compounds, irregular mono- and sesquiterpenes belonging to five families were also found composed of santolinane [Santolina triene (compound 4), isolyratone (compound 16) Fig. (7a), epi-isolyratol (compound 23) Fig. (7b), isolyratol (compound 25) Fig. (7b), lyrotal (compound 29) Fig. (7c), lyrotol (compound 30) Fig. (7d) and its ester (compounds 38, 40 and 44) Fig. (7d)], artemisane [Yomogi alcohol (compound 13), artemisia ketone (compound 22), artemesia alcohol (compound 26)] chrysanthemane [trans- and cischrysanthemyl alcohols (compounds 31 and 32)], lavandulane [Lavendulol (compound 33)] and sesquilavanoulane [(3, 9-dimethyl-6-iso-propyl-2Z and 2E, 7E, 9-decatrienal (compounds 49 and 50)]. Fig. (7) shows the essential oils obtained from Santolina Corsica Jordan et Fourr. Essential oil of S. corsica was found to possess antimicrobial activity against S. aureus and Campylobacter jejuni and lyratol was identified as the main compound responsible for antibacterial activity. The growth of P. aeruginosa, Enterobacter aerogenes and E. coli was not inhibited by the essential oil, whereas moderate activity was found against Listeria innocua. The oxygenated fraction, characterized by pre-eminence of lyratol (27.9%), 1,8-cineole (10.8%) and isolyratol (9.2%), showed better activity against S. aureus and C. jejuni. The 1, 8-cineole was also described previously to possess antibacterial activity against S. aureus [69] and moderate activity against C. jejuni [70]. Liu et al. [71] used lyratol rich fractions to investigate antibacterial activity against S. aureus and C. jejuni and concluded that antimicrobial properties of essential oil of S. corsica was due to lyratol. Many irregular monoterpenes including artemisia ketone, artemisia alcohol, artemisia triene, santolina triene, santolina alcohol, Yomogi alcohol, chrysanthemyl alcohol, lavandulol [72-75], and lyratol and lyratyl derivatives have been reported to present in Santolina oil [71].

8 Anti-Infective Agents in Medicinal Chemistry, 2009, Vol. 8, No. 3 10

6

8

4

Cichorium intybus

7

5

5 9

10

6

7

3

9

2

8

1

O

3

4

Isolyratone (Compound 16)

2 1

H

OH

Epi-isolyratol/isolyratol (Compound 23/25)

(a)

(b) 10

6

7

5 2

9 8

4

O 1

3

H

lyratal (Compound 29) (c) 10

6

7

5 2

9 8

4

3

R = OH R = OCOCH 3 R = OCOCH 2CH2 CH3 R= OCOCH2 CH(CH3)2

Shahid et al.

R 1

lyratol (Compound 30) lyratyl acetate (Compound 38) lyratyl butyrate (Compound 40) lyratyl isovalerate (Compound 44) (d)

Fig. (7). Essential oil from Santolina Corsica Jordan et Fourr.

Achillea clavennae Achillea clavennae, member of family Asteraceae, has a mythological background because it is named after Achilles, who used plants to heal wounds [76]. In modern Croatian traditional medicine, A. clavennae and its related species are frequently used against diarrhoea, abdominal pain, fever, common cold, influenza, and respiratory disorders. Its aerial parts are widely used in folk medicine for the preparation of remedies with anti-inflammatory, spasmolytic, hemostatic, digestive and cholagogue effects [77-79]. Essential oils from Achillea clavennae also exhibit antibacterial as well as antifungal properties [80-82]. Previous chemical studies on Achillea clavennae demonstrated the isolation of essential oils and flavonoids [83]. while Skoibui et al., [84] investigated these essential oils of A. clavennae for its antibacterial activity against respiratory tract pathogens. Maximum activity was observed against K. pneumoniae and penicillin-susceptible and penicillin-resistant Streptococcus pneumoniae. The oil showed strong activity against medically important respiratory pathogens including Haemophilus influenzae and P. aeruginosa, whereas Streptococcus pyogenes was found to be the most resistant organism. Chemical composition of the essential oil obtained from A. clavennae showed dominance of monoterpene hydrocarbons and their derivatives, while sesquiterpenes were also present in small quantities. The oil was characterized by high content of oxygen-containing monoterpenes camphor (29.5%) and comparatively smaller amounts of myrcene, 1, 8 cineole,  Caryophylleno, linalool and geranyl acetate. The major compounds eucalyptol (1,8cineole) and camphor are well-documented chemicals with pronounced antimicrobial activities.

Cichorium intybus, also belonging to family Asteraceae, has long been used in traditional medicine and is a strong antioxidant [85] which can be used for better digestion and while possessing diuretic properties [86]. Inspite of these reported medicinal properties the information on its antibacterial activity is fragmentary [87]. Previous phytochemical studies on C. intybus have reported isolation of inulin, tannins, and pectins from its roots, while cichorin has been isolated from its flower [88]. The well-known bitter taste of chicory is due to presence of sesquiterpene lactones [89]. Petrovic et al., [86] investigated antibacterial activity of water, ethanol, and ethyl acetate extract of C. intybus and found the ethyl acetate extract to be the most active. Water extract inhibited growth of Agrobacterium radiobacter species. tumefaciens, Erwinia carotovora, Pseudomonas fluorescens and P. aeruginosa. Surprisingly, E. coli was found to be resistant to all of the extracts tested while the root extract showed more intensive antibacterial activity as compared to whole plant extract. Eupatorium glandulosum In India, the Badagur, Irular and Toda tribal people of Nilgiris, use leaf paste of E. glandulosum (also a member of Asteraceae) to treat cuts and wounds. Previous phytochemical studies on Eupatorium species have resulted in the isolation of flavonols, glycosides [90, 91], while Sasikumar et al., [92] screened petroleum-ether, chloroform, ethyl acetate, methanol and aqueous extracts of E. glandulosum leaves for antibacterial properties and observed that the extracts showed significant concentration-dependent activity against Gram-positive bacteria (B. subtilis, S. aureus, S. pyogenes) and Gram-negative bacteria (K. pneumoniae, P. aeruginosa, S. typhi, E. coli) with MIC values ranging between 0.25-2.0 mg/mL. Uvaria hamiltonii In Indian traditional medicine, U. hamiltonii botanicals are used in treating minor infections. Previously reported phytochemicals include aristolactam alkaloids [93], a titerpene [94], steroids, polypeptides, flavonones, an aurone, a chalcone and tetrahydroxanthene [95]. Recently Asha et al. [95] obtained piperolactum C, goniopedaline, 6 hydroxystigmasta-4, 22-dien-3-one and mixture of cis- and trans-4-hydroxymelleins from extracts of U. hemiltonii stem bark and evaluated its antimicrobial properties. Among those purified compounds, Piperolactam C was found inhibitory to all the tested pathogens including A. hydrophilia, B. cereus, B. megaterium, B. subtilis, E. coli, Klebiella species, P. aeruginosa, S. paratyphi A, S. paratyphi B, Salmonella typhi, Sarcina lutea, Shigella boydi, S. sonnei, S. aureus, Vibrio cholerae and V. haemolyticus. In these studies, goniopedaline showed slightly less potency with a zone of inhibition of 15 mm against S. paratyphi A and B. subtilis. The mixture of cis- and trans-4-hydroxymelleins showed better activity against B. subtilis and S. sonnei, however, 6hydroxystigmasta-4, 22-dien-3-one showed mild activity only against A. hydrophilia and B. subtilis. They also investigated the cytotoxity of stem bark extracts of U. hemiltonii and observed that petroleum-ether, dichloromethane, metha-

Plant Natural Products as a Potential Source for Antibacterial Agents

nol extracts, were active and piperolactum C, a compound isolated demonstrated mild to moderate cytotoxicity against brine shrimp nauplii. Commiphora mukul C. mukul is a plant in the family Burseraceae and traditionally used as a mouth wash and dentifrice, for treating ulcers of the mouth and pharynx, and for foul and indolent ulcers. It is also used extensively in traditional ethnomedicine for wound healing in veterinary practice and as an ingredient of incense and perfume in religious and ceremonial chemistry [96]. In ancient history it has also used as the ‘Kyphi’ of Egyptians for embalming and fumigations [97]. Previous phytochemical studies on C. mukul have reported the presence of terpenoids [98-103], whereas Saeed et al. [96] reported isolation of seven sesquiterpenoids compound from the oleo-gum resin of the same plant. They also evaluated antimicrobial activities of the isolated compounds and showed that both the essential oil and chloroform extracts exhibited the most potent and persistent inhibitory activities against B. subtilis (ATCC 6633), E. coli (ATCC 8739), Sarcinia lutea (ATCC 9341), S. aureus (ATCC 6536), B. thuringiensis HD-1, S. typhi, S. paratyphii, S. boydii, S. dysenteriae, S. flexneri, S. sonnei, B. megaterium, K. pneumoniae, Microccocus roseus, M. leuteus, P. vulgaris, Pseudomonas aeruginosa, S. epidermidis and S. albus. Other notable compounds isolated from C. mukul include curzerene and furanoeudesma-1, 3-diene, which both showed inhibitory activities similar to the essential oil and CHCl3 extract, while 3 methoxy-10-methylene furano-germar-1-en6-one and 2-methoxy-4, 5-dihydrofurano-dien-6-one showed the least activity. Lindestrene, curzerenone and furanodien6-one all exhibited intermediate antimicrobial activity. Stereospermum zenkeri Stereospermum zenkeri is a medium size plant attaining a height of 10m and belongs to the family Bignoniaceae, native to Africa [104]. In Cameroon, Stereospermum species is used in traditional medicine, for bronchitis, while the roots and leaves are used cure fever and microbial infections. Previous phytochemical studies on Stereospermum genus reported the presence of several bioactive compounds, anthraquinones and lignans [105-107]. Lenta et al. [104] have reported two new anthraquinones, zenkequinone A (compound 1) and B (compound 2) together with a known sterequinone-P, p-coumaric acid and sitosterol-3-O--D glucopyranoside. Compound 1 was obtained as a yellow semisolid substance with, a molecular formula C19H16O3. Compound 2 was obtained as a yellow powder with molecular formula C19H16O3Na and was proposed that it could be a part of angular cyclisation of sterequinone F (compound 3). The antimicrobial activity of the isolated compounds was evaluated and zinkequinone B showed best activity with a MIC of 9.50
g/mL against P. aeruginosa. The antimicrobial activity of quinines may be linked to their properties of complex irreversibility with nucleophilic amino acids in proteins often leading to inactivation of the protein and loss of biological function [108].

Anti-Infective Agents in Medicinal Chemistry, 2009, Vol. 8, No. 3

9

Ravenia spectabilis Ravenia spectabilis is a member of the family Rutaceae. No significant study demonstrating components exists in the literature, although its ethnobotanical use, however, Sohrab et al. [109] was investigated using methanolic extracts of R. spectabilis. One principal component obtained was an alkaloid, arberinine, along with fraction comprising arborinine and r-fagarine, which were found to possess significant in vitro antibacterial activity. The activity was significant against B. cereus, B. megatirium and Vibrio mimicus with zones of inhibition of 28, 25 and 25 mm, respectively. VLC fractions of Ravenia (petroleum-ether-EtOAc in the ratio of 1:3) exhibited good activity against B. cereus, B. subtilis, A. hydrophilia, E. coli, S. paratyphii A, S. paratyphii B, Shigella dysenteriae and Vibrio mimicus. The purified compound arborinine demonstrated only mild antibacterial activity against E. coli and S. dysenteriae with zones of inhibition of 7 mm and 9 mm, respectively at a dose of 200
g/disc. Newly isolated constituents includes arborinine [110], r-fagarine [111], stigmasterol and stigmasta-4, 22diene-3-one, however, previously isolated constituents were comprised mainly of alkaloids [112, 113]. Abies webbiana Abies webbiana belongs to family Pinaceae and is used as a traditional medicine by people of West Bengal against hyperglycemia, conception, rheumatism and high grade fever [114]. Previous phytochemical studies demonstrated the presence of abeisin, methylbetuloside and betuloside from its leaves [115]. Recently Vishnoi et al. [114] isolated alkaloids, amino acids, flavonoids, saponins, tannins and steroids from the methyl alcohol extract of dried leaf powder of the same plant species. They further tested antimicrobial activities of the methanolic extract and found that maximum antibacterial activity was exhibited against S. aureus and S. typhi. However, it also had activity against M. luteus, S. epidermidis, E. coli, V. cholerae and S. dysenteriae. The extract also showed concentration dependent antifungal activity against Aspergillus niger and Candida albicans. Embelia ribes Embelia ribes is a member of the family Myrsinaceae. Various plant parts of this species have been reported to have traditional medicinal uses. Dried fruits of genus Embelia is used as a traditional anthelmintic, astringent, and as an alternative tonic in ascariasis. It is also been used as a medicament in scorpion sting and snake bites. The decoction is found to be beneficial in fever and diseases of chest and skin while infusion of its roots is often used for cough and diarrhoea. Aqueous extracts of the Embelia fruits showed antibacterial [116] as well as antifertility activities [117] while the seeds were found to possess antibiotic and antitubercular properties [117]. Embelin, a benzoquinone-derivative isolated from E. ribes, revealed anti-fertility [118], analgesic, anti-inflammatory, antioxidant and antitumor properties [119]. Previous studies demonstrated the presence of embelin, quercitol, christembine, a volatile oil [116] and vilangin [120].

10 Anti-Infective Agents in Medicinal Chemistry, 2009, Vol. 8, No. 3

Antibacterial potential of the embelin was studied [120] and was demonstrated that embelin displayed significant antibacterial activity at higher concentration (100 μg/disc). Significant activity of embelin was found against S. aureus, Streptoccocus pyogenes, S. flexneri, S. sonnei and P. aeruginosa while it showed moderate activity against S. typhi, S. boydii, P. mirabilis, E. coli and K. pneumoniae. Artocarpus heterophyllus Artocarpus heterophyllus belongs to the family Moraceae and is used in traditional medicinewhereby the pulp and seeds are used as a tonic and pectorial, and the roots in diarrhea and fever. The woody stem is used as a sedative in convulsions, while its leaf ash is applied to ulcers and wounds. Folkloric medicine also describes the leaves that are used to activate milk production in women and animals, which also acts a as antisyphilic and vermifuge [121]. Chemically, it has been demonstrated that Artocarpus possessed antibacterial flavones from the heartwood [122], antiplatelet flavones with antidiabetic activity. Lastly the leaves showed activity against Trichophyton mentagrophytes [123]. Previous studies on its constitutent phytochemicals demonstrated the presence of active constituents such as flavones [121, 122], Diels-Alder adducts [124] and titerpenoids [125]. Khan et al. [123] investigated the antimicrobial activities of crude methanolic extracts of the stem and roots,, bark, stem and root heart-wood, leaves, fruits and seeds of A. heterophyllus and also performed fractionation (partitioning with petrol, dichloromethane, ethyl acetate and butanol). It was demonstrated that fractionation improved the activity while the butanol fraction at a concentration 4 mg/disc of the root bark and fruits were the most active against bacteria while none of the fractions were active against fungi. Cuscuta reflexa and Corchorus olitorius Cuscuta reflexa is a member of the family Convolvulaceae and C. olitorius belongs to the family Tiliaceae. Traditionally Cuscuta reflexa stem are useful externally against itch and skin inflammation and internally in fevers [126] while C. olitorius seeds are used as purgatives [127]. Both of these plants are used in traditional tribal medicine as antifertility and anti-convulsive agents [128, 129]. Previously, several constituents were isolated and include steroids, flavonoids, soluble phenols (from C. reflexa stem) [130-133]. The cardenolide glycosides (from C. oliotorius seeds) [134] have also been isolated. Recently, antibacterial activity of C. reflexa stem and C. olitorius seed was investigated [135] with activity seen with the methanol fraction of C. reflexa stem (MECR) and C. olitorius seeds (MECO) at a concentration ranging 25-125 μg/mL and 50-150 μg/mL, respectively. They exhibited moderate broad spectrum antibacterial activity against Gram-positive bacteria (S. aureus, B. pumilus) and Gram-negative bacteria (S. typhi, S. typhimurium, Shigella boydii, S. sonnei, S. dysenteriae, P. aeruginosa, K. pneumoniae, E. coli and V. cholerae). Petroleum ether and CHCl3 fractions showed no such activity. Antibacterial activity of MECR and MECO were found to be concentration dependent with MECR at a dose of 125 μg/mL showing significant activity against S. aureus, S. boydii, P. aeruginosa, S. dysentriae and E. coli with zones of

Shahid et al.

inhibition ranging from 16-24 mm. MECO was most effective against S. aureus, B. pumilus, S. typhi, S. dysenteriae and E. coli with zones of inhibition ranging from 20-25 mm at a concentration of 150 μg/mL. Alstonia scholaris and Leea tetramera Alstonia scholaris is a member of the family Apocynaceae and L. tetramera belongs to the family Leeaceae. These are medicinal plants of East and South East Asia. Traditionally A. scholaris is used as febrifuge and tonic, for digestion, in liver and intestinal troubles and malaria, for enlarged spleen, in diarrhea and dysentery and as an anti-diabetic, anthelminthic, anti-epileptic as well as in gonorrhea, hypertension, asthma and lung cancer [136]. Species of Leea are used against guinea worm, fever, stomachache, expulsion of tapeworm, in dysentery, headache, skin infections, boils and wounds [136]. Previous phytochemical studies demonstrated the isolation of alkaloids, terpenoids [136, 137] from A. scholaris, while no phytochemical has been isolated from L. tetramera. Khan et al. [138] investigated the antimicrobial activity of crude methanolic extracts of leaves, stem and root barks of A. scholaris and L. tetramera on partitioning petroleum, ethyl acetate, and butanol fractions. They found that the butanol fractions of A. scholaris and the root bark of L. tetramera showed improved broad-spectrum antimicrobial activity while none of the fractions were found to be active against fungi. Antibacterial spectrum of both the plants was tested against B. cereus, B. coagulans, B. megasterium, B. subtilis, Lactobacillus caesi, Micrococcus leuteus, M. roseus, S. albus, S. aureus, S. epidermidis, Streptococcus faecalis, S. pneumoniae, S. mutans, A. tumefaciensi, C. freundii, E. aerogenes, E. coli, K. pneumoniae, N. gonorrhoeae, P. mirabilis, P. vulgaris, P. aeruginosa, S. typhi, S. typhimurium and Serratia marcescens. Tested fungi and protozoan agents includes A. niger, A. rubrum, A. versicolor, A. vitis, C. albicans, C. tropicalis, Cladosporium cladosporiods, P. notatum, Trichophyton mentagrophytes, T. tronsurum and Trichomonas vaginalis, respectively. Mosses In general, mosses are found to be resistant to the attack of bacteria, fungi, insects, and other trauma and thus they have several medicinal uses especially in China, Europe, and N. America [139]. Sphagnum moss (Sphagnum species) is known for its antibiotic activity and wound healing capacity. Previously detected phytochemicals from H. splendens comprised of biluteolin, phytenic acids and arachidonic acid [104]. Recently, Kang et al. [141] demonstrated antibacterial activities of a variety of different mosses including Bartramia pomiformis, Ceratodon purpureus, Dicranum scoparium, Eurhynchium pulchellum, Hylocomium splendens, Leucolepsis acanthoneuron, Neckera donglasii, Pleurozium schreberi, Rhacomitrium lanuginosum and Rhytidiadelphus triquetrus. It was observed that the methanolic extract of all mosses except R. lanuginosum, showed activity against Gram-positive MRSA, S. aureus, B. subtilis, Enterococeus faecium, whereas none of them showed activity against Gram-negative bacteria such as E. coli, P. aeruginosa and S. typhimurium. Two strains and their extractss, L. acanthoneuron and H. splendans showed stronger activity

Plant Natural Products as a Potential Source for Antibacterial Agents

especially against Staphylococci whereas ethyl acetate fractions of H. splendens was found to be active against all Gram-positive bacteria tested with high activity (MIC 2.19 μg/mL) against S. aureus. Extracts of B. pomiformis, C. purpureus and N. douglasii demonstrated enhancement of antibacterial activity against Staphylococci by UV-A light irradiation. Andrographis paniculata Andrographis paniculata is the herbaceous plant belonging to family Acanthaceae and native to India and Sri Lanka Where it is of great therapeutic value and is widely referred to as ‘wonder drug’ in local folkloric medicine. Commonly known as ‘Kalmegha’, it is reported to possess antihepatotoxic, antibiotic, antimalarial, antihepatitis, antithrombogenic, antiinflammatory, antivenom, and antipyretic properties. Andrographis paniculata plant extracts are known to possess variety of pharmacological activities and its bitter active principle, Andrographolide, which is the chief constituent extracted from the leaves of this plant, is a bitter water-soluble lactone, that was isolated in the pure form [142] (8a). Andrographolide from A. paniculata may inhibit HIVinduced cell cycle deregulation while 1, 2-dihydroxy-6, 8dimethoxy-xanthone, isolated from Andrographis paniculata possessed in vitro activity against P. falciparum. Herbal preparations containing Andrographis panuculata have also been shown to have antihepatotoxic activity [143].The ethanol extract with its isolated diterpenes, andrographolide and neoandrographolide from the aerial parts of this plant, showed significant antihepatotoxic action against Plasmodium berghei K173-induced hepatic damage in Mastomys natalensis [144]. Antibacterial and antifungal activities have also been demonstated by aqueous extracts. Andrographolide and arabinogalactan proteins isolated from A. paniculata are comparable in terms of growth inhibition of B. subtilis, E. coli, P. aeruginosa and C. albicans to some known antibiotics, including streptomycin, gentamycin and nystatin [145]. A. paniculata was also clinically tested for its antiviral activity. Clinical studies suggested that this plant may be effective as an early treatment of uncomplicated acute upper respiratory tract infections in the patients tested. The ethanol extract of A. paniculata alone or in combination with the ethanol extract of A. senticocus appeared to be more effective than placebo [146]. The active constituents, andrographolide and neoandrographolide, have also been reported to have anti-allergic effects, due presumably to its mast cell stabilizing activity, the same as for the antiallergic drug, disodium cromoglycate. Neoandrographolide was reported to be more potent than the andrographolide. All three compounds also demonstrated significant inhibition of passive cutaneous anaphylaxis [147]. Immunomodulating effects were also shown by a methanol extract, where andrographolide, 14-deoxyandrographolide, (see in Fig. 8b) and 14deoxy-11, 12 didehydroandrographolide were isolated from this plant.

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Zingiberaceae, which is native to tropical South Asia. It has been used traditionally as a spice and to treat illnesses such as appendicitis, asthma, itch, rheumatism, abdominalgia, anaemia, hypertension, diarrhea, and dysentery. Curcumin is the main phenolic constituent of the genus especially in the rhizome of tumeric Curcuma domestica. Although C. domestica, also called C. longa, has not been used traditionally for anticancer purposes, although recent investigations showed that this plant has promising cytotoxic effects, mainly ascribed to the compound curcumin (see in Fig. 9). The active constituents of turmeric are the flavonoid curcumin and other volatile oils including tumerone, atlantone, and zingiberone. Its anticancer mechanism includes induction of apoptosis and reduction of the cell cycle progression and thus prevents cancerous cell growth [148, 149]. In vitro and in vivo studies demonstrated that it suppressed carcinogenesis of the liver, kidney, colon, and breast [150, 151]. While members of the plant family Zingiberaceae are generally regarded as safe for human consumption, these species are excellent candidates for development of novel therapeutic agents [152]. Both curcumin and the oil fractions suppress growth of several bacteria such as Streptococcus, Staphylococcus, and Lactobacillus [153]. The aqueous extract of turmeric rhizomes has been shown to possess antibacterial activity [154] while curcumin also prevents growth of Helicobacter pylori Cag A+ strains in vitro [155]. O

O HO

O

O

HO

HO

HO

HO

(a)

(b)

Fig. (8). Andrographis paniculata derived antibacterial compounds. O H3CO HO

O OCH3 OH

Fig. (9). Curcuma longa derived antibacterial compounds.

Curcuma longa

Ethanol extracts of C. longa lead to inhibition of DNA polymerase II and induction of apoptosis [156] and also improves morning stiffness and joint swelling in arthritis patients. Studies conducted to investigate the antimicrobial activity of ethyl acetate, methanol and water extracts of Curcuma longa against Methicillin-resistant Staphylococcus aureus (MRSA) and ethyl acetate extracts were found to be the most active markedly lowering the MICs of ampicillin and oxacillin against MRSA. In the bacterial invasion assay, intracellular invasion of MRSA was significantly decreased in the presence of 0.125-2 mg/mL of C. longa extract compared with the control group [157].

Curcuma longa, commomly known as turmeric, is a rhizomatous herbaceous perennial plant of the family

Ether and chloroform extracts and the crude oil of C. longa have antifungal effects against Aspergillus flavus, A.

12 Anti-Infective Agents in Medicinal Chemistry, 2009, Vol. 8, No. 3

parasiticus, Fusarium moniliforme and Penicillium digitatum [158-162]. The ethanol extracts of the rhizomes has anti-Entamoeba histolytica activity. Curcumin has antiLeishmania activity in vitro [163]. Several synthetic derivatives of curcumin have anti-L. amazonensis effect [164] while anti-Plasmodium falciparum and anti-L. major effects of curcumin have also been reported [165]. Curcumin also shows anti-human immunodeficiency virus (HIV) activity by inhibiting the HIV-1 integrase needed for viral replication [166, 167]. Finally, curcurmin also inhibits UV light induced HIV gene expression [168]I delineating the role curcurmin and its analogues have for the potential development of novel drug entities against HIV.

Shahid et al. [6]

[7] [8] [9] [10] [11] [12]

CONCLUSION Existing novel antibacterial compounds for contemporary clinicians are limited in numbers, more specifically, the available antibiotics are facing the threat of antibacterial drug resistance. Hence there is a real need to search for novel antibacterial compounds to combat the resistance problem. In recent years more research has been performed exploring the newer plant natural products, isolating newer and more novel substances with antimicrobial potential including many which are discussed in this review. However further research is required to validate their antibacterial potential on a battery of clinical and multidrug-resistant bacteria, especially using the active principles elaborated in the present review. Many of the compounds mentioned in this review could also undergo chemical modificatgion to more active chemical species, thus serving as a guide for future medicinal chemistry and drug design efforts. It is emphasized here that in the future natural products chemistry will definitely provide a platform for further research and findings in the realm of bioactive antibiotics. ACKNOWLEDGEMENTS The authors wish to thank Dr. Nafeesur Rehman, Reader, Section of Analytical Chemistry, Department of Chemistry, AMU, Aligarh for critically reading the manuscript. M. Shahid is grateful to Department of Science & Technology, Ministry of Science & Technology, Government of India for awarding “Young Scientist Project Award” (FT/SR-L111/2006). A. Shahzad is also thankful for the award of similar “Young Scientist Project Award” (SR/FT/L-23/2006). The authors also wish to thank Dr. Mark L. Nelson, Editor in Chief of this journal, for editing and thoughtful suggestions concerning this manuscript. REFERENCES [1] [2] [3]

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