Allium_Review22222.pdf

What makes Allium species effective against pathogenicmicrobes?

Virginia Lanzotti Giuliano Bonanomi

Felice Scala

Received: 18 January 2013 / Accepted: 17 April 2013

Springer Science+Business Media Dordrecht 2013

Abstract The antimicrobial activity of garlic

(Allium sativum L.) has been known since ancient

times. The first citation dates back to the Egyptian

period of fifteenth century BC when garlic was

reported to be used in folk medicine as a remedy for

microbial infections. Scientific investigations on gar-

lic started in 1858 with the work of Pasteur who first

noted antibacterial properties of garlic extracts. From

that date to the discovery of antibiotics, garlic has been

used against amoebic dysentery and epidemic diseases

such as typhus, cholera, diphtheria, and tuberculosis.

But what makes garlic and Allium species effective

against pathogenic microbes? The volatile allicin and

other thiosulfinates, giving pungency to Allium plants,

are well-studied antimicrobial agents. The thiosulfi-

nates can decompose to form additional sulfur

constituents, including diallyl, methyl allyl, and

dipropyl mono-, di-, tri- e tetra-sulfides, and (E)- and

(Z)-ajoene without losing antimicrobial activity.

Besides these compounds, onion and garlic are

characterized by polar compounds of steroidal and

phenolic origin, often glycosilated, not pungent and

more stable during cooking, showing also antimicro-

bial activity. Recently, there has been increasing

scientific attention given to such compounds. Nitrogen

organic compounds, like alkaloids and polypeptides,

have also been isolated from these plants and have

shown antimicrobial activity. In this paper, the liter-

ature about the major volatile and non-volatile organic

compounds of garlic and other Allium plants has been

reviewed. Particular attention is given to the com-

pounds possessing antimicrobial activity and to the

correlation between the observed activity and the

chemical structure of the tested compounds.

Keywords Garlic Onion Thiosulfinates Saponins Phenolics Antimicrobial activity

Introduction

A great variety of chemical compounds with antimi-

crobial activity, traditionally known as secondary

metabolites, are produced by higher plants. Thousands

of diverse natural products, often involved in plant

defense against pest and pathogens, have been iden-

tified including terpenoids, saponins, phenolics and

phenylpropanoids, pterocarpans, stilbens, alkaloids,

glucosinolates, tiosulfinates and indoles among many

others (Dixon 2001). The phytochemical diversity of

plant antimicrobial compounds has been previously

reviewed by examining their involvement in constitu-

tive (Wittstock and Gershenzon 2002) and inducible

chemical defenses (Hammerschmidt 1999), mecha-

nisms of plant resistance (Morrisey and Osbourn

V. Lanzotti (&) G. Bonanomi F. ScalaDipartimento di Agraria, Universita` di Napoli Federico

II, Via Universita` 100, 80055 Portici, Napoli, Italy

e-mail: [email protected]

123

Phytochem Rev

DOI 10.1007/s11101-013-9295-3

1999) and fitness cost (Heil 2002). The potential

exploitation of such molecules for the control of plant

pathogens (Dixon 2001) has also been evaluated. The

genus Allium includes a great number of species

(between 600 and 750) (Stearn 1992; Jiemei and

Kamelin 2000), from which many antimicrobial

compounds have been extracted and identified.

The antimicrobial activity of extracts and oils

from garlic (Allium sativum), the most studied

species belonging to this genus, has been known

since ancient times. The first citation of this plant is

found in the Codex of Ebers (1550 BC), an Egyptian

medical papyrus reporting several therapeutic for-

mulas based on garlic as a useful remedy for a

variety of diseases such as heart problems, headache,

bites and worms (Block 1985). Cloves of garlic have

been found in the tomb of Tutankhamen and in the

sacred underground temple of the bulls of Saqqara.

Egyptians thought garlic increased endurance and

they assumed large quantities of it. Raw plants were

routinely given to asthmatics and to those people

suffering bronchial-pulmonary complaints. Later on,

garlic was known by the Greeks and Romans, who

used it like an important healing agent just as it is

still used today by most of the people in the

Mediterranean region (Lanzotti 2005). Besides gar-

lic, other Allium species (e.g. onion, shallot, leek,

chive, elephant garlic) are a rich source of phytonu-

trients, useful for the treatment or prevention of a

number of diseases, including cancer, coronary heart

disease, obesity, hypercholesterolemia, diabetes type

2, hypertension, cataract and microbe infection

(Lanzotti 2006, 2012).

Scientific research on these plants started in the

second half of the nineteenth century with the work of

Louis Pasteur who in 1858 first noted antibacterial

properties of garlic (Pasteur 1858). In 1932, Albert

Schweitzer treated amoebic dysentery in Africa with

garlic and, before the discovery of antibiotics, it was

also used for several epidemic diseases (e.g. typhus,

cholera, diphtheria, and tuberculosis). Recent research

has shown that garlic extracts and oils are effective

against a plethora of saprophytic, human- and plant-

pathogenic virus (e.g. Weber et al. 1992), bacteria (e.g.

Naganawa et al. 1996), fungi (e.g. Yoshida et al. 1987)

and protozoa (e.g. Millet et al. 2011). However, only

in the middle of the last century, Cavallito and Bailey

(1944) identified the most abundant and, among the

most potent, antimicrobial compound from garlic, the

thiosulfinate allicin (Fig. 1). Subsequent investiga-

tions attributed the antimicrobial properties of garlic to

allicin and other organosulfur compounds. However,

more recent studies on Allium species identify natural

compounds with antimicrobial activity of different

chemical classes, including saponins, flavonoids,

phenols, alkaloids and also peptides and proteins

(Fig. 1).

In this work we examine the chemical nature and

complexity of antimicrobial compounds discovered in

Allium plants, giving particular attention to the

correlation between their activity and chemical

structure.

Thiosulfinates(allicin)

Saponins & Sapogenins(alliogenin) Flavonoids (quercetin)

N-oxides & N-amides

Fig. 1 Schematicrepresentation of major

chemical classes of natural

compounds from Alliumspecies with antimicrobial

activity. These natural

compounds have been

isolated from the different

plant tissues (roots, bulbs,

leaves and flowers) and

seeds

Phytochem Rev

123

Allicin, ajoene and other organosulfur compounds

Allicin (diallyl thiosulfinate) (1b, Fig. 2) (Cavallito

and Bailey. 1944) is not present in garlic bulbs.

However, when tissue is damaged, the precurson alliin

(S-allylcysteine sulfoxide) (1a, Fig. 2), that is present

in garlic bulbs at a concentration ranging from 5 to

14 mg g-1, immediately is transformed into allicin by

the enzyme alliinase. Figure 2 shows allicin biosyn-

thesis starting from L-cysteine that for further reaction

with L-glutamic acid and S-2-propenyl carboxylic

acid, after decarboxylation, oxidation and isomeriza-

tion, gives rise to the close precursor alliin. This last by

enzymatic catalysis of alliinase affords the corre-

sponding sulfenic acid intermediate whose autocon-

densation in water phase results in the formation of

allicin.

Figure 3 reports the chemical structure of the

antimicrobial sulfoxide and sulfide compounds (2

15). This class of compounds was found first by

Wertheim (1844) and later on by Semmler who

identified the correct disulfide structure of the main

component of garlic (1982a) and onion (1982b)

distilled oil. Fifty years later, it was demonstrated that

these compounds are absent when the bulbs are frozen

in dry ice, pulverized, and extracted with acetone. The

garlic powder, obtained by this procedure, did not

have any pungency which, however, appeared after

the addition of water. When the powder was treated

with a hydroalcoholic solution, the enzyme was

inactivated and the disulfide compounds were not

found. These results demonstrate that the pungency of

garlic and Allium plants is associated with the sulfur

compounds which constitute up to 5 % of the dry

weight of the plant. These compounds originate from

allicin (1b) and thiosulfinates (e.g. 1623, Fig. 4),

which are quite unstable because of their thioester

bond, and give rise to further reaction during the

extraction and isolation procedures to form more

stable sulfoxides and sulfides (215, Fig. 3). All these

compounds are characterized by small terminal alkyl

chains, from one to three carbon atoms, connected to

sulphur atoms at different oxidation states.

The terminal alkyl chain could be also unsaturated

thus giving the 1-propenyl (named allyl from Allium)

or the 2-propenyl residue. This last group is present

with Z and E configurations and thus the compound

exists as a mixture of the Z and E isomers (e.g. 1819,

2021 and 2223, Fig. 4), because of a sigmatropic

rearrangement (Block 1985). This may also happen for

inner propenyl chains as in the case of ajoene, a

sulfoxide and sulfide compound, that has been isolated

in the E and Z isomers (2 and 3, respectively, Fig. 3)

and of its analogue 10-devinylajoene also isolated in

the two E and Z forms (14 and 15).

In nature, many plants, to avoid self-toxicity,

store antimicrobial compounds in the inactive forms

of non-toxic precursors. During pathogen attacks

SCO2H

O NH2S

OH S S

OAlliinase

Sulfenic acidIntermediate

Alliin (1a) Allicin (1b)

H2O

HSCO2H

NH2L-Glu

L-Cys

HSCO2H

NH Glu

SCO2H

NH GluCO2H

SCO2H

NH Glu

SCO2H

NH GluO

L-Glu L-Cys

Ox

- CO2

double bondIsomerization

condensation

L-Glu S-2-carboxylpropyl L-Cys

Fig. 2 Allicin biosynthesis starting from L-cysteine that forfurther reaction with L-glutamic acid and S-2-propenyl carbox-

ylic acid after decarboxylation, oxidation and isomerization

gives rise to the close precursor alliin. This last by enzymatic

catalysis of alliinase affords the corresponding sulfenic acid

intermediate whose autocondensation in water phase results in

the formation of allicin

Phytochem Rev

123

and/or when tissues are damaged, enzymes that

convert precursors into antimicrobial compounds are

made available (Hallahan 2000). In this way,

antimicrobial compounds are locally produced and

accumulated only when and where it is necessary

for defense against pathogens. Allicin (1b, Fig. 2),

although volatile, quite unstable and having a low

water solubility, is a potent antimicrobial compound.

It is able to inhibit at low concentrations, with an

LD50 often within the range of 320 lg ml-1, many

fungi, gram-positive and gram-negative bacteria,

pathogenic protozoa and also viruses (Table 1).

Antifungal activity of allicin was clearly demon-

strated by Yamada and Azuma (1977) against

several important genera of human pathogens

including Candida, Cryptococcus, Trichophyton,

Epidermophyton and Microsporum. Allicin can act

synergistically with synthetic fungicides. An early

study found that streptomycin and chloramphenicol

synergize with allicin in inhibiting Mycobacterium

tuberculosis (Gupta and Viswanathan 1955). Jonkers

et al. (1999) reported a synergistic interaction

between the antibiotic vancomycin and allicin in

the inhibition of several antibiotic-resistant entero-

cocci. A similar synergistic interaction was reported

between the cuprous ion, largely used as a broad-

spectrum fungicide, and allicin in the inhibition of

the yeast Saccharomyces cerevisiae (Ogita et al.

2005). The bactericidal activity of allicin has been

reported against at least 25 saprophytic and patho-

genic bacteria such as Bacillus spp., Enterococcus

spp., Escherichia coli, Helicobacter pylori, Salmo-

nella typhimurium, Staphylococcus aureus and Vib-

rio cholera (Table 1). Recently, Cutler and Wilson

(2004) reported that allicin was effective against

methicillin-resistant S. aureus strains.

Fig. 3 Sulfoxide andsulfide compounds from

Allium

Fig. 4 Thiosulfinatecompounds from Allium

Phytochem Rev

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Table 1 List of organic sulfur compounds from the genus Allium with related antibacterial, antifungal, antiparasitic and antiviralactivities

Species name Antimicrobial compounds Activity References

A. sativum

A. ursinum

Allicin (1b) Antifungal

Aspergillus flavus

Aspergillus fumigatus

Aspergillus niger

Aspergillus terreus

Candida albicans

Candida krusei

Candida neoformans

Candida tropicalis

Cryptococcus sp.

Epidermophyton foccosum

Microsporum gypseum

S. cerevisiae

Torulopsis glabrata

Trichophyton ferrugineum

Trichophyton mentagrophytes

Trichophyton rubrum

Yamada and Azuma (1977), Yoshida

et al. (1987), Shadkchan et al.

(2004), Ogita et al. (2005), Bagiu

et al. (2012)

Antibacterial

Acinetobacter baumanii

Bacillus dysenteriae

Bacillus enteriditis

Bacillus morgani

Bacillus paratyphosus

Bacillus subtilis

Bacillus typhosus

Enterococcus durans

Enterococcus faecalis

Enterococcus faecium

E. coli

H. pylori

Klebsiella pneumonia

Mycobacterium tubercolosis

Proteus mirabilis

P. aeruginosa

S. typhimurium

Shigella flexneri

Shigella dysenteriae

S. aureus

Streptococcus hemolyticus

Streptococcus pyogenes

Streptococcus viridans

V. cholera

Cavallito and Bailey (1944), Gupta

and Viswanathan (1955), Feldberg

et al. (1988), Ankri and Mirelman

(1999), Jonkers et al. (1999), OGara

et al. (2000), Culter and Wilson

(2004)

Phytochem Rev

123

Table 1 continued


Antiparasitic

Crithidia fasciculate

Entamoebe histolytica

Giardia lamblia

Leishmania major

Leptomonas colosoma

Spironucleus vortens

Mirelman et al. (1987), Ankri and

Mirelman (1999), Millet et al.

(2011)

Antiviral

Herpes simplex virus type 1


Parainfluenza virus type 3

Rhinovirus type 2

Vaccinia virus

Vesicular stomatitis virus

Weber et al. (1992)

A. sativum E- and Z-Ajoene (2, 3) Antifungal

Alternaria solani

Alternaria tenuissima

Alternaria triticina

A. niger

C. albicans

Candida valida

Colletotrichum sp.

Curvularia sp.

Fusarium lini

F. oxysporum

Fusarium semitectum

Fusarium udum

Hanseniaspora valbyensis

Kluyveromyces lactis

Paracoccidioides brasiliensis

Pichia anomala

S. cerevisiae

Schizosaccharomyces pombe

Tinea corporis

Tinea cruris

Tinea pedis

Yoshida et al. (1987), San-Blas et al.

(1989), Singh et al. (1990),

Naganawa et al. (1996), Yoshida

et al. (1998), Ledezma et al. (1999),

Ledezma et al. (2000)

Antibacterial

B. cereus

B. subtilis

E. coli

K. pneumoniae

Lactobacillus plantarum

M. luteus

Mycobacterium phlei

Naganawa et al. (1996), Yoshida et al.

(1998)

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123

Table 1 continued


P. aeruginosa

S. aureus

Streptomyces griseus

Xanthomonas maltophilia

Antiparasitic

Plasmodium berghei

S. vortens

Trypanosoma cruzi

Urbina et al. (1993), Perez et al.

(1994), Millet et al. (2011)

Antiviral




Rhinovirus type 2

Vaccinia virus


Weber et al. (1992)

A. sativum Diallyl monosulphide (DAS) (4) Antifungal

A. flavus

A. fumigatus

A. niger

C. albicans

Candida glabrata

C. krusei

Tsao and Yin (2001)

Antibacterial

Camplobacter jejuni

K. pneumoniae

L. monocytogenes

S. typhimurium

S. aureus

Chen et al. (1999), Tsao and Yin

(2001), Yin and Cheng (2003)

A. sativum

Allium odorum

A. cepa

Diallyl disulphide (DADS) (5) Antifungal

A. flavus

A. fumigatus

A. niger

C. albicans

C. glabrata

Tsao and Yin (2001), Kim et al.

(2004)

C. krusei

Candida utilis

Antibacterial

B. cereus

Camplobacter jejuni

H. pylori

K. pneumoniae

L. monocytogenes

S. typhimurium

S. aureus

Naganawa et al. (1996), Chen et al.

(1999), OGara et al. (2000),

Tsao and Yin (2001), Yin and

Cheng ((2003)), Kim et al.

(2004)

Phytochem Rev

123

Table 1 continued


A. sativum

Allium odorum

A. cepa

Diallyl trisulphide (DATS) (6) Antifungal

A. flavus

A. fumigatus

A. niger

C. albicans

C. glabrata

C. krusei

C. utilis

Penicillium expansum

Yoshida et al. (1987), Tsao and

Yin (2001), Kim et al. (2004),

Liu et al. (2009)

Antibacterial

Cryptococcus neoformans

H. pylori

S. aureus

Shen et al. (1996), OGara et al.

(2000), Tsao and Yin (2001),

Kim et al. (2004)

Antiparasitic

E. histolytica

G. lamblia

Trichomonas vaginalis

Trypanosoma brucei

Trypanosoma congolese

Trypanosoma equiperdum

Trypanosoma evansi

Lang and Zhang (1981), Lun et al.

(1994)

A. sativum

Allium odorum

A. cepa

Diallyl tetrasulphide (DATTS) (7) Antifungal

A. flavus

A. fumigatus

A. niger

C. albicans

C. glabrata

C. krusei

C. utilis

Tsao and Yin (2001), Kim et al.

(2004)

Antibacterial

H. pylori

S. aureus

Tsao and Yin (2001), OGara et al.

(2000), Kim et al. (2004)

A. sativum

A. cepa

Dipropyl disulfide (8); Dimethyltrisulfide (9); Diethyl trisulfide(10); Diproyl trisulfide (11);Dimethyl tetrasulfide (12);Diethyl tetrasulfide; Dipropyl

tetrasulfide (13)

Antifungal

C. utilis

Antibacterial

S. aureus

Kim et al. (2004)

Phytochem Rev

123

Table 1 continued


A. sativum E-10 devinylajoene (14); Z-10devinylajoene (15)

Antifungal

C. valida

H. valbyensis

K. lactis

P. anomala

S. cerevisiae

S. pombe

Antibacterial

B. cereus

B. subtilis

E. coli

K. pneumoniae

M. luteus

M. phlei

P. aeruginosa

S. aureus

X. maltophilia

Yoshida et al. (1998), Yoshida

et al. (1999a)

A. sativum Allyl methyl thiosulfinate (16) Antiviral




Rhinovirus type 2

Vaccinia virus


Weber et al. (1992)

A. sativum Methyl allyl thiosulfinate (17) Antiviral




Rhinovirus type 2

Vaccinia virus


Weber et al. (1992)

A. sativum S-(Z, E)-1-propenyl ester (18, 19);2-propenesulfino thioic acid S-methyl ester (20, 21);methanesulfino thioic acid S-(Z,E)-1-propenyl ester (22, 23)

Antifungal

S. cerevisiae

S. pombe

Antibacterial

B. cereus

B. subtilis

E. coli

K. pneumoniae

M. luteus

P. aeruginosa

S. aureus

X. maltophilia

Yoshida et al. (1999b)

Phytochem Rev

123

Allicin has a low toxicity towards mammalian cell

cultures with negative effects generally observed at

concentrations higher than 60 lg ml-1 (Ankri andMirelman 1999). The different responses of microbial

and mammalian cells to allicin is likely related to the

action mechanisms of this compound. The antimicro-

bial activity of allicin has been associated with the

inhibition of sulfhydryl-dependent enzymes (Wills

1956) such as alcohol dehydrogenase, thioredoxin

reductase, and RNA polymerase. In many cases, the

addition of both cysteine and glutathione reduced the

inhibitory effects of allicin because these two com-

pounds react with allicin disulfide bond, thus prevent-

ing cell damage. Glutathione occurrence in

mammalian cells may explain their limited sensitivity

to allicin compared to microbial cells which contain a

very small amount of this compound (Davis 2005).

Ajoene takes its name from the Spanish word ajo

which means garlic. It is formed when allicin is

dissolved in several solvents including edible oils

(Block et al. 1984). Both E- and Z-ajoene exhibited

broad-spectrum antimicrobial activity against gram-

positive and gram-negative bacteria (Yoshida et al.

1987; Naganawa et al. 1996), fungi (Yoshida et al.

1998; Ledezma et al. 2000) and protozoa (Perez et al.

1994; Millet et al. 2011; (Table 1). Moreover, the few

available studies indicate that ajoene has a more potent

antiviral activity compared to allicin and other Allium

derived organosulfur compounds (Weber et al. 1992).

As reported for allicin, the addition of cysteine greatly

reduces the inhibitory effect of ajoene, likely as a

result of the interaction between the amino acid and

the disulfide bonds of the compound (Naganawa et al.

1996).

Antimicrobial activity has been reported for several

allyl sulfide compounds (Table 1 and 47, Fig. 3) and

seems to be related to the number of disulfide bounds,

i.e. DATTS [ DATS [ DADS [ DAS (Tsao andYin 2001).

Saponins

Saponins are widespread in the plant kingdom (Sparg

et al. 2004; Vincken et al. 2007), as well as within the

genus Allium. In this review we found that saponins

have been extracted and identified from at least 38

different Allium species (Table 2). The majority of

available studies focus on common, cultivated species

such as garlic (A. sativum), onion (Allium cepa), leek

(Allium porrum), chinese onion (Allium chinense) and

chives garlic (Allium tuberosum). However, studies on

rare or wild species are also available (e.g. Allium

cyrilii, Allium leucanthum, Allium minutiflorum;

Table 2).

The isolated saponins are based on spirostanol,

furostanol and cholestanol aglycon (Fig. 5) (Lanzotti

2012). Structurally, they are C27 sterols in which

cholesterol has undergone modifications to produce a

spiroketal. In particular, the spiroketal function is

derived from the cholesterol side-chain by a series of

oxygenation reactions affording hydroxylation at C-16

and at one of the terminal methyls, and then producing

a ketone function at C-22. This intermediate is

transformed into the hemiacetal, an unstable interme-

diate that undergoes glycosilation reaction at C-26

thus obtaining the spirostanol aglycon or further

reaction giving rise to the corresponding spiroketal,

that is the spirostanol aglycon. This can be also

obtained by hydrolysis of the furostanol aglycon with

the releasing of the sugar unit(s) at C-26.

The cholesterol aglycon has been only found in A.

porrum and Allium nigrum, while the other skeletons

are both present at almost the same level (Lanzotti

2012). From the data in the literature it seems that the

spirostanol skeleton is typical of garlic taxa, while the

furostanol skeleton is typical for onion taxa. Figure 6

reports the more common sapogenins (2428) found in

these plants that constitute the spirostanol aglycon of

the corresponding saponins. Hydroxylation on the

skeletal core has been commonly found at position 2,

3, 5 and 6 as shown in Fig. 6.

Saponins from Allium species has many biological

properties including antispasmodic, cytotoxic, hae-

molytic, anti-inflammatory and antitumour activity

(Sparg et al. 2004). Surprisingly, only a few studies

have investigated their antimicrobial properties.

In this review, we found that only 9 out of 62 studies

concerning Allium saponins reported significant anti-

fungal activity (Table 2). Among these, Barile et al.

(2007) reported three saponins, named minutosides

A-C tested against several fungal plant pathogens,

including Botrytis cinerea, Fusarium oxysporum and

Rhizoctonia solani. In particular, minutoside B (29,

Fig. 7) was the major saponin plant tissue

(83.5 mg kg-1) and also showed the highest activity

in inhibiting spore germination and hyphal growth of

the tested fungi. Recent studies further reported that

several saponins from the common garlic var.

Phytochem Rev

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Table 2 List of saponins from the genus Allium and related biological activities

Species name Compounds Activity References

Alliumampeloprasum

Six spirostanol saponins Antifungal

Mortierella ramanniana

Cytotoxic

Sata et al. (1998)

A. cepa Three furostanol saponins Antifungal

Alternaria alternata

A. niger

B. cinerea

F. oxysporum

Mucor sp.

Phomopsis sp.

R. solani

Sclerotium cepivorum

Trichoderma atroviride

T. harzianum

Lanzotti et al. (2012b)

A. leucanthum Five spirostanol saponins Antifungal Mskhiladze et al. (2008b)

A. minutiflorum Two furostanol and three spirostanol saponins Antifungal

A. alternata

Alternaria porri

B. cinerea

F. oxysporum

F. oxysporum f.sp. lycopersici

Fusarium solani

P. ultimum

R. solani

T. harzianum

Barile et al. (2007)

A. porrum Four spirostanol saponins Antifungal

F. culmorum

Carotenuto et al. (1999)

A. sativum Ten furostanol and two spirostanol saponins Antifungal

B. cinerea

T. harzianum

Lanzotti et al. (2012a)

A. sativum One furostanol saponin Antifungal

C. albicans

Matsura et al. (1988)

A. ursinum Two spirostanol saponins Antifungal

C. glabrata

Candida parapsilosis

Microsporum canis

Trichophyton mentagrophytes

Cytotoxic

Sobolewska et al. (2006)

Allium vineale Nine spirostanol saponins Antifungal

P. expansum

Molluscicidal

Biomphalaria pfeifferei

Chen and Snyder (1989)

Allium fistulosum Nine furostanol saponins Antihypoxic Lai et al. (2010)

Alliummacrostemon

Three furostanol saponins Antiplatelet Ou et al. (2012)

A. sativum One furostanol and three spirostanol saponins Antiplatelet Peng et al. (1996b)

A. cepa Eleven furustanol saponins Antispasmodic Corea et al. (2005)

Phytochem Rev

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Table 2 continued


Allium hirtifolium Five furostanol and four spirostanol saponins Antispasmodic Barile et al. (2005)

A. chinense Two spirostanol saponins and one sapogenin Antitumor; Cytotoxic Baba et al. (2000)

Allium macleanii Five spirostanol and one cholestanol saponins Antitumor Inoue et al. (1995)

A. porrum Four sapogenins Antitumor Carotenuto et al. (1997)

Allium senescens Two spirostanol saponins Antitumor Inoue et al. (1995)

A. chinense Six spirostanol saponins ATPase inhibition Kuroda et al. (1995)

Allium giganteum One spirostanol and two furostanol saponins cAMP phosphodiesterase inhibition Mimaki et al. (1994)

A. macrostemon Eight furostanol saponins Cellular Ca2? activity Chen et al. (2006)

Allium aflatunense Five spirostanol saponins Cytotoxic Mimaki et al. (1999a)

Alliumkarataviense

One furostanol, five spirostanol saponins and

one sapogenin

Cytotoxic Mimaki et al. (1999c)

A. leucanthum Seven spirostanol saponins Cytotoxic Mskhiladze et al. (2008a)

A. nigrum Eight spirostanol and two cholestanol saponins Cytotoxic Jabrane et al. (2011)

A. porrum Six spiristanol and two cholestanol saponins Cytotoxic Fattorusso et al. (2000)

A. tuberosum One spirostanol saponin Cytotoxic Sang et al. (2002)

A. macrostemon Nine furostanol saponins Cytotoxic, antitumour Chen et al. (2007)

A. macrostemon Two furostanol saponins Cytotoxic; antitumour Chen et al. (2009)

A. ampeloprasum One spirostanol saponin Haemolytic, anti-inflammatory,gastroprotective

Adao et al. (2011a); Adao

et al. (2011b)

A. aflatunense One spirostanol saponin Not assessed Kawashima et al. (1991)

Allium albanum Five saponins Not assessed Ismaiiov et al. (1976)

Allium albiflorus One saponin Not assessed Ismailov and Aliev (1976)

Alliumalbopilosum

Two spirostanol and four cholestanol saponins Not assessed Mimaki et al. (1993)

A. ascalonicum Four furostanol saponins Not assessed Kang et al. (2007)

Alliumatroviolaceum

One sapogenin and one spirostanol saponin Not assessed Zolfaghari et al. (2006)

A. cepa var.tropeana

Eight furostanol saponins Not assessed Dini et al. (2005)

A. chinense Two furostanol saponins Not assessed Peng et al. (1996a)

Allium cyrillii Two spirostanol saponins Not assessed Tolkacheva et al. (2012)

Allium elburzense Eight furostanol and five spirostanol saponins Not assessed Barile et al. (2004)

Allium erubescens One spirostanol saponins Not assessed Chincharadze et al. (1979)

A. fistulosum Five spirostanol saponins Not assessed Do et al. (1992)

A. fistulosum Seven sapogenins Not assessed Lai et al. (2012)

A. giganteum One spirostanol saponin Not assessed Kawashima et al. (1991)

A. giganteum One sapogenin Not assessed Khristulas et al. (1970)

Allium jesdianum One spirostanol saponins Not assessed Mimaki et al. (1999b)

A. karataviense Three spirostanol saponins Not assessed Gorovits et al. (1973)

A. karataviense Four spirostanol saponins Not assessed Vollerner et al. (1978)

Alliumnarcissiflorum

Two furostanol saponins Not assessed Krokhmalyuk and Kintya

(1976)

Allium nutans Two furostanol and two spirostanol Not assessed Akhov et al. (1999)

Alliumostrowskianum

One cholestanol saponin Not assessed Mimaki et al. (1993)

Allium rotundum One furostanol and one spirostanol saponin Not assessed Maisashvili et al. (2012)

Allium rubellum Four saponins Not assessed Ismaiiov et al. (1976)

Allium schubertii One furostanol and three spirostanol saponins Not assessed Kawashima et al. (1993)

Phytochem Rev

123

Voghiera (Lanzotti et al. 2012a), and onion (Lanzotti

et al. 2012b) have antifungal activity versus several

plant pathogens. In Fig. 7 the chemical structures of

voghieroside A (30) and ceposide B (31) are reported

both based on furostanol aglycon. Sobolewska et al.

(2006) demonstrated that two steroidal saponins from

Allium ursinum inhibited in vitro two Candida species.

Indeed, Allium species can produce a great diversity of

saponins that are stored in plant cells and have in vitro

antifungal activity. However, their role in plant

resistance against pathogens still has to be elucidated.

This contrasts with saponins from other plant species

Table 2 continued


Alliumsphaerosephalon

One furostanol saponin Not assessed Mimaki et al. (1996)

Allium triquetrum Ten furostanol saponins Not assessed Corea et al. (2003)

A. tuberosum Two spirostanol saponins Not assessed Sang et al. (1999a)

A. tuberosum Three furostanol saponins Not assessed Sang et al. (1999b)

A. tuberosum Four spirostanol, three furostanol, and onecholestanol saponins

Not assessed Sang et al. (2003)

A. tuberosum One spirostanol saponins Not assessed Zou et al. (2001)

Alliumturcomanicum

Five sapogenins and one saponin Not assessed Pirtskhalava et al. (1979)

Allium waldsteinii Three sapogenins and five saponins Not assessed Gugunishvili et al. (2006)

Note that only in few cases (9 out of 62) antifungal activity was assessed

Fig. 5 Aglyconbiosynthesis in Alliumsaponins

Phytochem Rev

123

such as oat (Avena sativa) and tomato (Salanum

lycopersicum) for which the role of avenacin and a-tomatine in plant defense has been clearly demon-

strated (Morrisey and Osbourn 1999; Martin-

Hernandez et al. 2000). Bowyer et al. (1995) reported

that the fungus Gaeumannomyces graminis var. ave-

nae is able to infect oat because it produces the

enzyme avenacinase that detoxifies avenacins, the

antifungal oat saponins. To clarify the biological

significance of Allium saponins in plant defense, future

studies should assess if these compounds accumulate

in plant tissues at concentrations which can inhibit

pathogens in vivo, and identify the molecular mech-

anisms involved in their antimicrobial activity.

In contrast with organosulfur compounds, Allium

saponins have weak or negligible antibacterial activity.

Barile et al. (2007) tested five saponins on eight fungi

(Table 2), seven bacteria (Xanhomonas campestris pv.

campestris, Agrobacterium tumefaciens, Streptomyces

turgidiscabies, Pseudomonas syringae pv. syringae,

Clavibacter michiganensis pv. michiganensis, Bacil-

lus mycoides and P. fluorescens) and an oomycete

(Pythium ultimum). The five saponins inhibited the

growth of all fungi but were ineffective against

Pythium and the tested gram-negative and gram-

positive bacteria. The different response of fungi,

oomycetes and bacteria to saponins is likely related to

Fig. 6 Sapogenins isolated from Allium

Fig. 7 Examples ofsaponins isolated from

A. minutiflorum, A. sativumvar.Voghiera, and A. cepa

Phytochem Rev

123

differences in their membrane structure. It has been

hypothesized that saponins exhibit their antimicrobial

activity by forming complexes with the sterols that are

present in the membrane of microorganisms, thus

damaging the membrane with consequent cell collapse

(Morrisey and Osbourn 1999). The limited toxicity of

saponins to pathogens such as the oomycetes Pythium

and Phytophthora may depend on the lack of sterols in

their membranes (Arneson and Durbin 1968; Barile

et al. 2007). Some reports indicate that saponins from

non-Allium plant species such as Acacia (Mandala

et al. 2005), Hedera (Cioaca et al. 1978), Medicago

(Avato et al. 2006) and Yucca (Wang et al. 2000) can be

inhibitory against bacteria. However, comparative

studies between fungi and bacteria usually indicate

that fungi are more sensitive than bacteria (e.g. Avato

et al. 2006; Barile et al. 2007), although the mecha-

nisms underlying the different sensitivities are still

unclear.

Data obtained from antifungal tests carried out with

analogous saponins (Barile et al. 2007; Lanzotti et al.

2012a, b) allowed the definition of some structure

activity relationships that are summarized in Fig. 8,

where the pharmacophoric elements for this activity are

highlighted. In particular, positive effects have been

found for hydroxyls at positions 3 and 6, and a spirostane

aglycone, while negative effects have been found for a

furostane aglycone, for oxygenation at C-5, and increas-

ing number of sugars at C-3. However, further studies are

needed to clarify the mechanism of action of saponins and

to determine how these compounds are detoxified by

pathogenic fungi resulting in the degradation of their

chemical structure with the loss of activity.

Despite the fact that in Allium species organosulfur

compounds, saponins, phenols, alkaloids and antimi-

crobial proteins occur together within plant tissues,

most studies have addressed only the antifungal

activity of single molecules. A recent study reported

that the antifungal activity of some saponins from A.

cepa against the plant pathogen B. cinerea and the

biocontrol agent Trichoderma harzianum can be

synergically enhanced when they are supplied in

combination (Lanzotti et al. 2012b).

Other organic compounds with antimicrobial

activity

Although the antimicrobial activity of Allium species

has been ascribed to organosulfur compounds and,

more recently, to saponins, other antimicrobial com-

pounds that belong to different chemical classes have

been discovered (Fig. 1; Table 3).

Several proteins and peptides with antimicrobial

activity have been found. For instance, the 10 kD

AceAMP1 protein from A. cepa inhibited twelve

fungal and two bacterial species (Phillippe et al. 1995).

Wang and Ng (2002, 2004) discovered ascalin and

allicepin, two peptides with antifungal activity from A.

ascalonicum and A. cepa, respectively. In addition, it

has been found in garlic and leek roots and bulbs the

presence of high amounts of two N-feruloyl amides,

N-feruloytyrosine (32) and N-feruloyltyramine (33)

(Fig. 9) (Fattorusso et al. 1999). Because the infusion

of garlic roots is used in traditional medicine as

antielminthic, the possible antimicrobial activity of

these two compounds was evaluated. Both compounds

were active against the pathogen Fusarium culmorum

with ED50 of 20 and 22 lg/ml, respectively. Recently,ODonnell et al. (2009) discovered from A. stipitatum

Fig. 8 Key pharmacophoric elements for the antifungal activ-ity of Allium saponins

Phytochem Rev

123

Table 3 List of other organic compounds with antimicrobial activity extracted from the genus Allium


A. ascalonicum Ascalin (peptide) Antifungal

B. cinerea

Wang and Ng (2002)

A. cepa Allicepin (peptide) Antifungal

B. cinerea

F. oxysporum

Mycosphaerella arachidicola

Physalospora piricola

Wang and Ng (2004)

A. cepa Quercetin (Flavon) (41) Antibacterial

B. cereus

E. coli

L. monocytogenes

M. luteus

P. aeruginosa

S. aureus

Santas et al. (2010)

A. cepa Kaempferol (Flavon) (39) Antibacterial

M. luteus

S. aureus

Santas et al. (2010)

A. cepa Protein (10 kDAceAMPl) Antifungal

Alternaria brassicola

Ascochyta pisi

B. cinerea

Colletotrichumlindemuthianum

F. culmorum

F. oxysporum f.sp. pisi

F. oxysporum f.sp. lycopersici

Nectria haematococca

Phoma betae

Pyrenophora tritici-repentis

Pyricularia oryzae

Verticillium dahliae

Antibacterial

Bacillus megaterium

Sarcina lutea

Phillippe et al. (1995), Tassin et al.

(1998)

Alliumfistolosum

Fistulosin (octadecyl

3-hydroxyindole)

Antifungal

F. oxysporum

F. solani

Fusarium moniliforme

Verticillium dahliae

Penicillium roqueforti

Aspergillus oryzae

Magnaporthe grisea

Rhizopus oryzae

Phay et al. (1999)

Phytochem Rev

123

three pyridine-N-oxide alkaloids (3436, Fig. 9) with

potent antibacterial activity on fast-growing species of

Mycobacterium, methicillin-resistant S. aureus, and a

multidrug-resistant (MDR) variants of S. aureus.

Flavonoids are ubiquitous in photosynthesising

cells and are commonly found in fruits and vegetables.

The common flavonoids found in garlic and onion are

reported in Fig. 10 (3742) with their content in fresh

bulbs. Although preparations containing these com-

pounds have been used for centuries to treat human

diseases, only recently this class of natural products is

becoming the subject of research about infectious

diseases, and many groups have isolated and identified

the structures of flavonoids possessing antifungal,

antiviral and antibacterial activity. In particular,

quercetin (41) and kaempferol (39), the major flavo-

noids from A. cepa, showed antibacterial activity to

Bacillus cereus, E. coli, Listeria monocytogenes,

Micrococcus luteus, Pseudomonas aeruginosa and S.

aureus (Table 3). Concerning the mechanism of

action, it seems that the activity of quercetin and the

flavonoids with B-ring hydroxylation, could be

partially attributed to the inhibition of DNA gyrase

(Ohemeng et al. 1993), although other mechanisms

could not be excluded.

Conclusions

From the ancient Egyptian period to the discovery of

antibiotics, garlic has been used as an antimicrobial

remedy in folk medicine. Scientific investigations

have demonstrated that besides the well-studied

sulphur compounds there are other classes of com-

pounds, e.g. saponins, flavonoids, nitrogen com-

pounds and peptides, that make garlic and Allium

species effective against pathogenic microbes. Despite

the great number of antimicrobial compounds isolated,

Allium species may still be an important source of such

molecules. Isolation and identification of other anti-

microbial compounds should be pursued to meet the

urgent need for new classes of drugs. However, the

development of more effective antimicrobial agents

or a group of agents can also be achieved through

Table 3 continued


A. porrum Chitinase protein (34 kDa) Antifungal

Cercospora musae

C. lindemuthianum

Trichoderma viride

Trochoderma hamatum

Vergawen et al. (1998)

A. sativum Allivin (36 kDa protein) Antifungal

B. cinerea

M. arachidicola

Physalospora piricola

Wang and Ng (2001)

A. sativum

A. porrum

N-amides (3233) Antifungal

F. culmorum

Fattorusso et al. (1999)

Alliumstipitatum

Pyridine-N-oxide alkaloids (3436) Antibacterial

S. aureus

M. phlei

M. smegmatis

Mycobacterium fortuitum

ODonnell et al. (2009)

A. tuberosum Chitinase-like protein (36 kDa) Antifungal

B. cinerea

Coprinus comatus

F. oxysporum

M. arachidicola

R. solani

Lam et al. (2000)

Phytochem Rev

123

structural modifications of the already known com-

pounds. Existing structureactivity data suggest that it

might be possible, for example, to prepare potent

antibacterial saponins by obtaining compounds with a

spirostanol skeleton and oxygenation at C-3 and C-6.

Further studies are also required to completely under-

stand the mechanism of action of the known com-

pounds. This is an important step to be able to use

these antimicrobial compounds to the maximum of

their potential. For instance, it has been shown that

these compounds may synergistically increase their

activity when they work together. Future studies can

address this issue by testing combinations of antimi-

crobial compounds (e.g. organosulfur compounds and

saponins) that co-occur in plant tissues. In addition,

characterization of the interaction between the anti-

microbial compounds and their target sites could

reduce resistance mechanisms thus allowing the

design of second generation inhibitors that are more

active and less toxic.

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What makes Allium species effective against pathogenic microbes?AbstractIntroductionAllicin, ajoene and other organosulfur compoundsSaponinsOther organic compounds with antimicrobial activity

ConclusionsReferences

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