European Journal of Medicinal Chemistry 143 (2018) 922e935

Contents lists available at ScienceDirect

European Journal of Medicinal Chemistry

journal homepage: http://www.elsevier.com/locate/ejmech

Review article

An overview of natural antimicrobials role in food

Aurelia Magdalena Pisoschi a, *, Aneta Pop a, Cecilia Georgescu b, Violeta Turcuş c,
Neli Kinga Olah c, Endre Mathe c, d
a
University of Agronomic Sciences and Veterinary Medicine of Bucharest, Faculty of Veterinary Medicine, 105 Splaiul Independentei, 050097, Sector 5,
Bucharest, Romania
b
”Lucian Blaga” University of Sibiu, Faculty of Agriculture Science, Food Industry and Environmental Protection, Dr. I. Ratiu str.7-9, 550012, Sibiu, Romania
c
Vasile Goldiş Western University of Arad, Faculty of Medicine, Department of Life Sciences, Liviu Rebreanu str.91-93, 310414, Arad, Romania
d
University of Debrecen, Faculty of Agriculture and Food Sciences and Environmental Management, Institute of Food Technology, Bo €szo
€rmenyi út 138, H-
4032, Debrecen, Hungary

a r t i c l e i n f o a b s t r a c t

Article history: The present paper aims to review the natural food preservatives with antimicrobial properties empha-
Received 4 June 2017 sizing their importance for the future of food manufacturing and consumers' health. The extraction
Accepted 28 November 2017 procedures applied to natural antimicrobials will be considered, followed by the description of some
Available online 2 December 2017
natural preservatives' antimicrobial mechanism of action, including (i) membrane rupture with ATP-ase
activity inhibition, (ii) leakage of essential biomolecules from the cell, (iii) disruption of the proton
Keywords:
motive force and (iiii) enzyme inactivation. Moreover, a provenance-based classification of natural an-
Biopreservation
timicrobials is discussed by considering the sources of origin for the major natural preservative cate-
Foodborne pathogens
Essential oils
gories: plants, animals, microbes and fungi. As well, the structure influence on the antimicrobial
Antimicrobial peptides potential is considered. Natural preservatives could also constitute a viable alternative to address the
Bacteriocins critical problem of microbial resistance, and to hamper the negative side effects of some synthetic
Bacteriolytic enzymes compounds, while meeting the requirements for food safety, and exerting no negative impact on
nutritional and sensory attributes of foodstuffs.
© 2017 Elsevier Masson SAS. All rights reserved.

Contents

1. Introduction: biopreservation and fighting foodborne microbial pathogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 922

2. Extraction procedures of natural antimicrobial compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 923
3. Mechanisms of action of antimicrobials in food . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 924
4. Plant - derived natural antimicrobials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 925
5. Natural antimicrobial agents of animal origin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 927
6. Natural preservatives from microbial sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 928
7. Natural preservatives from algae and mushrooms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 929
8. Several illustrative applications of natural antimicrobials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 930
9. Critical conclusive aspects and prospects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 930
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 932

1. Introduction: biopreservation and fighting foodborne

microbial pathogens

Many foodborne diseases are caused by ingestion of food

contaminated with microbial pathogens. Many studies are focused
* Corresponding author. on counteracting the action of such food related pathogens and on
E-mail address: [email protected] (A.M. Pisoschi).

https://doi.org/10.1016/j.ejmech.2017.11.095
0223-5234/© 2017 Elsevier Masson SAS. All rights reserved.
 A.M. Pisoschi et al. / European Journal of Medicinal Chemistry 143 (2018) 922e935 923

extending the shelf life of processed food, considered of pivotal extract, freeze dried powder or oil extract, and they all could inhibit
importance, being tightly related to issues like food poisoning and lipid oxidation, increasing shelf life of chicken sausage [12]. The
consumers' health, together with food waste reduction and food application of natural antimicrobials for foodstuff preservation can
business cost-effectiveness. also be associated with other non-thermal treatments [13e16]. It
Various food preservation methods and technologies have been seems therefore likely that employing natural antimicrobials is
developed, to comply with the demands of consumers regarding becoming a viable alternative to diminish health hazards and
microbiological safety, nutritional values and sensory properties of economic shortcomings in case of microorganisms-contaminated
foodstuffs. The thermal processing of foods implies subjecting them foodstuffs. The demand for natural antimicrobial alternatives,
to temperatures comprised between 60 - 100
C for several seconds replacing synthetic compounds, is expected to increase steadily as
to minutes. During this treatment, thermal energy is transferred to the negative influence exerted by some synthetic preservatives on
food in large amounts that can have sometimes undesired organ- the consumers' health has been demonstrated [17,18]. Moreover,
oleptic and nutritional effects. Moreover, synthetic food pre- stressful daily routines together with unbalanced nutrition, and the
servatives like nitrates, benzoates, sulfites, sorbates, formaldehyde consequent increase of the incidence of several chronic diseases, all
are also known for their life-threatening side effects [1]. The use of plead for foods that satisfy health-conscious consumers' demands
sulphites can result in various allergic reactions in case of sulphite for preventive and/or therapeutic nutrition. Actually, a novel trend
hypersensitive consumers [2]. Surprisingly, the allergic reactions of functional foods brings together multiple bioactive compounds
vary on a large scale starting from asthma, urticaria, abdominal with health-promoting and antimicrobial effects [19]. In this
pains, nausea, diarrhea as well as seizures and anaphylactic shocks respect, we are facing a rather challenging controversy: the newly
resulting in death, that most probably depend on the individual's identified bioactive compounds should feature antimicrobial
general health condition. The use of synthetic phenolic antioxi- specificity only to the food borne pathogens, and they are expected
dants is corroborated with carcinogenic effects likely to occur, not to influence negatively the consumer's own microbiome.
although the use of butylated hydroxyanisole (BHA) and butylated The emerging problematics regarding the negative impact
hydroxytoluene (BHT) has been reduced [3]. The above-mentioned exerted by some synthetic preservatives on the health of con-
health risks concerns are pleading for the application of natural sumers versus the benefits imparted by natural antimicrobials and
food preservatives [4]. As an alternative to chemical and thermal their specificity to food borne pathogens, all these considerations
preservations, and in the same time for ensuring food safety while are leading to the requirement for more systemic research to
not affecting food quality standards (nutritional and sensory-flavor, evaluate the toxicity and mechanism of action of natural pre-
odor, color, texture), in sum all these imperatives, have led to an servatives, and to elaborate proper safety regulations [20]. Along-
ever increasing interest for defining novel preservation methods side the food safety concerns, the focus on natural antimicrobials is
like biopreservation and bioprotection [5]. also justified by the wrong use and incorrect handling of antibiotics
Biopreservation is focused on the utilization of natural pre- that led to the development of multidrug resistant microorganisms,
servatives from sources like bacteria, fungi, plants, animals, having including foodborne pathogens unaffected by currently used anti-
the ability to ensure food safety due to their antimicrobial activity biotics and by the conventional applied food processing and pres-
exerted against a wide spectrum of foodborne pathogens [6]. ervation techniques [6]. It seems that we are just at the beginning of
Moreover, secondary metabolites with antimicrobial activity are an important quest for natural biopreservatives with antimicrobial
produced by fruits, vegetables, seeds, herbs and spices, milk, eggs, properties. Therefore, the identification and utilization of such
animal tissues, and microorganisms such as bacteria and fungi [7]. natural antimicrobials, and their characterization with respect to
Plant/animal-derived preservatives, natural or controlled micro- safety, specificity and efficacy, do represent key objectives for food
flora, such as lactic bacteria and the corresponding antibacterial and drug research and industries.
compounds like lactic acid, bacteriocins proved able to delay lipid
oxidation, inhibited color loss, prolonged storage life and ensured 2. Extraction procedures of natural antimicrobial compounds
food security. Biopreservation has been shown effective in case of
raw and cooked meat that requires the application of different Effective extraction and purification procedures are critical for
natural extracts obtained from herbs, spices, fruits and vegetables isolation and application of natural antimicrobials intended for
inhibiting lipid oxidation, preserving color and improving shelf food related usage. Initially, the preparation techniques were
stability. Such benefits were assigned to bioactive compounds like mainly represented by steam distillation and hydro-distillation,
phenolics (flavonoids and non-flavonoids), phenolic terpenes and while recently non-conventional methods such as supercritical
tannins [8,9]. It has also been demonstrated that several herb and fluid extraction providing improved solubility and mass transfer are
vegetal extracts could behave like antioxidants, antimicrobials, applied. The precise control of working parameters such as tem-
anti-diabetics, anti-carcinogens, flavorings, beverages and re- perature and pressure enables extraction of various components,
pellents, all being properties leading to multiple applicability in even in cases when a specific compound is targeted [21]. Other
food manufacturing. Plant-based derivatives containing different methods include microwave assisted extraction and ultrasounds
bioactive compounds were divided in two major categories like (i) extraction that decrease the extraction time. Furthermore, such
vegetable or essential oils (obtained from olive, canola, soy, sun- techniques proved their efficiency in obtaining better quantitative
flower, linseed, avocado, grape seed, oregano, rosemary, coriander and qualitative yields for volatile oils. Interestingly, the essential
seed), and (ii) extracts (obtained from grape seed, green tea, olive oils obtained from plants including spices/herbs did also feature
leaf, cranberry, pomegranate, broccoli, cocoa leaf, lemon balm), antimicrobial potential, and are obtained by various methods, such
though, other categories might be considered too [9]. It has been as steam, dry, cold or vacuum distillation [22,23]. There are two
shown that the oregano essential oil significantly reduced lipid and main vegetal origin compound classes with important antimicro-
protein oxidation, and improved color stability of raw and cooked bial activity: polyphenols and essential oils [24]. These compound
chicken breast meat [10]. Similarly, the coriander seed oil is very classes were extracted by classical methods until the past 2-3 de-
well known for its antimicrobial activity against Gram-positive and cades, when the new and high performance extraction methods
Gram-negative bacteria, some yeasts, dermatophytes and fila- were translated from laboratory to industrial scale with many ad-
mentous fungi [11]. Some plants can contain both major de- vantages regarding the extraction time, extracts quality and the
rivatives, and it has been reported that garlic can be used like fresh obtained yield.
924 A.M. Pisoschi et al. / European Journal of Medicinal Chemistry 143 (2018) 922e935

It has been assessed that extraction techniques that involve yield are influenced by pressure and temperature that can be
chemical or thermal treatments can alter the active ingredients widely adjusted for a supercritical solvent like carbon dioxide. This
yield, functionality, or natural features, or can produce unsafe extraction method is environment-friendly, and the utilized low
compounds [25,26]. Direct extraction applied to fruits and vege- temperature will preserve the compounds' bioactive potential [40].
tables is very straightforward and can preserve the native structure Another modern method is the ultrasound extraction that enables
and composition of active ingredients. Direct extracts from guava an intensive mass transfer, improves the penetration and capillary
and xoconostle pears (Opuntia matudae) confirmed their efficacy effects, but has a low reproducibility [35]. A comparative study
against Salmonella spp. and E. coli O157:H7 [27,28]. Direct extrac- performed on extracts obtained by the canonical Soxhlet and cold
tion applied to fruits and vegetables involves mere mechanical extraction methods clearly demonstrated the cold extraction's su-
treatment without any chemical treatment, heating, or concentra- periority due to a better preservation of bioactive antioxidant
tion. Water extraction is used to extract mainly phenolics from compounds, leading to an increased antimicrobial effect [41].
seeds and leaves [29]. Thermal treatment of hydrosoluble musca- It seems therefore likely that several extraction methods were
dine (Vitis rotundifolia) seed extracts resulted in enhanced antimi- developed in order to obtain bioactive compounds with antimi-
crobial activity and acidity, leading to an increase in total phenolics crobial properties. The selectivity of such methods falls short when
[29]. It has been assessed that alternative methods relying on it comes about extracting a single component, though recently, the
ultrahigh-temperature, far-infrared radiation, or enzyme treatment emphasis is put on minimal extracts with high antimicrobial effi-
can determine the dissociation of polymeric compounds with the ciency and on minimizing interferences with consumers' health.
subsequent release of the corresponding low molecular-weight
components that may lead to a reduction in the antimicrobial ef- 3. Mechanisms of action of antimicrobials in food
ficiency. It has been concluded that direct extraction or juice
extraction may avoid alterations of the structure and activity of Plant derived phenolic compounds act by the alteration of mi-
natural antimicrobials [29e31]. crobial cell permeability, therefore allowing the loss of bio-
Chitin extraction from shrimp wastes can be achieved by molecules from the inside of cells (for example ribose and sodium
chemical and biological methods. The former involve acid treat- glutamate) [7,22]. Phenolics interfere with cell membrane func-
ment (demineralisation being performed with mineral or organic tionality as they interact with membrane proteins inducing their
acids-hydrochloric acid, nitric acid, sulphuric acid, acetic or formic structure and function alteration. Affected membrane functions are
acid), or alkaline treatment meaning deproteinisation with sodium related to electron transport, nutrient uptake, synthesis of proteins
hydroxide. Biological extractive procedures imply demineralisation and nucleic acids, and enzyme activity [7,22].
with lactic bacteria and deproteinisation with proteases of bacterial It has been shown that thymol, eugenol and carvacrol disrupt
origin. Chitin deacetylase-producing bacteria or alkali are used, the cell membrane, inhibit ATP-ase activity, followed by a release of
aiming at chitin deacetylation to obtain chitosan [32]. Alga extracts intracellular adenosine triphosphate and other cell components.
can be obtained by employing solvent extraction that use meth- Carvacrol and thymol increase membrane permeability [42,43] by
anol, ethanol, diethyl ether, hexane, chloroform and water [33]. dissolution into the phospholipid bilayer aligning between the fatty
The microwave-assisted extraction methods are dated back to acid chains [44]. Alkyl substitution into the aromatic nucleus [17] is
the 1980’. Initially there were developed a few techniques for this another process underlying the antibacterial activity of phenolics.
type of extraction like the pressurized microwave-assisted extrac- Nevertheless, in the case of more stable phenolics like the ethers
tion, solvent-free microwave-assisted extraction [34,35] and anethole or myricistin, the release of phenoxyl radicals able to react
microwave-assisted hydrodistillation [36e39], respectively. All of with alkyl substituents does not happen. This observation was
them were having the main advantage of a reduced duration time linked to the scarce antimicrobial activity of nutmeg, fennel, or
and a better mass transfer due to the microwave power. The ad- parsley essential oils [45]. Moreover, it was stated that the anti-
vantages of microwave-assisted extraction were eloquently microbial activity of phenolics depends on concentration: at low
demonstrated in case of olive leaves polyphenols [34]. The study concentration, phenols inhibit microbial enzyme activity, whereas
showed that the water extraction using microwaves has a better at high concentrations they induce denaturation of proteins [7].
selectivity, the extraction time and labor expenses were reduced, With respect to the influence of phenolic structure on the
yet the yield was better and the polyphenols' profile was not antimicrobial activity, it has also been demonstrated that functional
different from the one specific for the cold extraction. groups such as hydroxyl groups promote electron delocalization,
Proving the advantages of microwave-assisted hydrodistillation and can act as proton exchangers, diminishing the pH gradient
in comparison with the classical hydrodistillation, represented the across the cytoplasmic membrane of bacterial cells. This causes the
subject of many papers in the past decade. Such comparative decay of proton motive force, depletion of ATP pool, and is subse-
studies have shown similar yields, reduced extraction time and quently followed by cell death [6,46].
energy expenditure, suggesting that the microwave-assisted It has been proved that the antimicrobial activity of onion and
hydrodistillation is an environment-friendly technology too. The garlic isothiocyanates is due to the inactivation of extracellular
microwave extraction generated essential oil profiles of thyme enzymes through oxidative dissociation of -S-S- bonds. It was
(Thymus vulgaris L.), rosemary (Rosmarinus officinalis), basil (Oci- established that the mediator of this antimicrobial activity is the
mum basillicum L.) and mango flowers (Mangifera indica). These thiocyanate radical, endowed with high reactivity [6,47,48].
profiles were similar to those obtained by classical hydro- Lipids inactivate microorganisms primarily by disrupting the
distillation, though the rupture of glandular cells' walls was more bacterial cell membrane, hindering DNA replication or inhibiting
efficient. Moreover, the antimicrobial activity of rosemary essential other intracellular targets. Fatty acids with long carbon chains have
oil obtained by microwave-assisted extraction had an increased been described as having a more powerful inhibitory effect than
efficiency in comparison with the significantly diminished inhibi- short chain fatty acids. Interestingly, a higher inhibitory effect was
tion area of classical essential oil [36e39]. assigned to unsaturated fatty acids, than to saturated correspond-
Despite many advantages, the solvent assisted extraction's ma- ing compounds [7,49]. Medium and long chain unsaturated fatty
jor inconvenience is related to health hazards so that recently, the acids acted more efficaciously against Gram positive, than against
supercritical fluid extraction is gaining popularity. The extracts Gram negative bacteria [49]. It has been asserted that the most
obtained by this method are solvent-free, while the selectivity and active saturated fatty acids possess 10 or 12 carbon atoms in the
 A.M. Pisoschi et al. / European Journal of Medicinal Chemistry 143 (2018) 922e935 925

chain, and their antibacterial potential presents a decreasing trend, Oregano and thyme essential oils featured pronounced bacte-
with either diminution or elongation of the chain [49]. riostatic and bactericidal properties. The irreversible damage of
The mechanism of action of antimicrobial peptides has been E. coli O157:H7 cells was noticed in 1 min, by applying the bacte-
studied, and although the cell membrane is considered a main ricidal concentration of oregano essential oil [77]. The volatile
target, recent studies have also identified intracellular targets [50]. terpenes carvacrol, p-cymene, g-terpinene, and thymol were
Antimicrobial peptides adopt amphipathic structures, interacting shown to be responsible for the antimicrobial potential of oregano,
with the microbial cell membrane. Membrane rupture in some thyme, and savory. The antimicrobial activity of sage and rosemary
locations results in the leaching out of essential cell biocomponents was assigned to borneol and other phenolics present in the terpene
[51]. The antimicrobial activity of bacteriocins relies on pore gen- fraction [15,78]. Essential oils of Thymus danensis and Thymus spp.
eration in the cytoplasmic membrane of the targeted microor- (Elam) flowers were tested, and exerted antibacterial activity
ganism. The result is the loss of low molecular mass intracellular against Listeria monocytogenes. It was established that the use of
components and ions, and the disruption of the proton motive force these flower-derived essential oils resulted in more significant in-
[52]. This mechanism can explain why nisin acts less effectively on hibition against bacteria, than the other plant parts extracts. The
Gram-negative bacteria, since the outer membrane hinders the assessed minimal inhibitory concentration (MIC > 50% growth
access of this molecule [53e55]. Studies focused on nisin, prove inhabitation) for Thymus danensis and Thymus spp. were 700 and
that this bacteriocin first diffuses through the cell wall of Gram- 1700 mg/ml, respectively [79]. The essential oils of Pinus pinea and
positive bacteria. Moreover, it was asserted that the Gram- Pinus brutia proved significant antimicrobial activities on Micro-
positive bacterial cell wall can behave as a molecular sieve coccus luteus and Bacillus subtilis, insecticidal potential on Ephestia
against nisin, and that this ability depends on cell wall composition, kuehniella eggs, phytotoxic potential on Lactuca sativa, Lepidium
thickness, or hydrophobic character [56]. Nisin associates with the sativum, and Portulaca oleracea, as well as antioxidant capacity [80].
cytoplasmic membrane of the target microorganism, establishing Another study focused on the grape seed and pine bark extracts
essentially electrostatical interactions with the negatively charged inhibitory effect exerted against E. coli O157:H7, S. Typhimurium,
phosphate groups present in the structure of membrane phos- and L. monocytogenes in ground beef. The results point that these
pholipids [57,58]. The outcome is the disruption of membrane natural extracts can be employed in association with other pre-
function, and the prevention of spores development by inhibition serving methods to diminish pathogenic population and to
of the swelling process of germination. Leakage of intracellular improve ground beef quality [81]. Grape seed extract in combina-
metabolites and disruption of the membrane potential is the tion with nisin, malic acid, and EDTA proved enhanced antimicro-
consequence of cytoplasmic membrane permeation by nisin [59]. bial activity against the development of L. monocytogenes and E. coli
O157:H7 [82].
4. Plant - derived natural antimicrobials The water extract of olive leaf at 0.6% (w/v) caused death of
almost all bacterial cells within 3 h, while 1.25% and 15% (w/v)
The main compounds present in essential oils, that impart concentrations of olive leaf extract were necessary to cause death of
antimicrobial properties of plants including herbs and spices are Dermatophytes and Candida albicans, respectively [83]. The anti-
phenolics (flavonoids and non-flavonoids), terpenes, aliphatic al- bacterial and antifungal activity of olive leaves extract was due to
cohols, aldehydes, ketones, organic acids, saponins, thiosulfinates, phenolic compounds like caffeic acid, verbascoside, rutoside, api-
glucosinolates [7,15,17,42,60e64]. Edible, medicinal, herbal plants genin 7-O-glucoside, luteolin 7-O-glucoside and luteolin 40 -O-
and the corresponding essential oils and byproducts such as hy- glucoside, oleuropein [84]. Nonphenolic compounds found in
drosols, as well as secondary metabolites, are able to delay or essential oils such as allyl isothiocyanate in garlic oil [85] proved
inhibit the development of bacteria, yeast, and molds [15,64,65]. also efficacious against Gram-negative bacteria. In particular, allyl
Essential oils are natural mixtures of hydrocarbons (terpenes), isothiocyanate acts also as antifungal [86].
oxygen-containing (alcohols, aldehydes, ketones, carboxylic acids, Caffeic acid, chlorogenic acid, and protocatechuic acid were the
esthers, lactones) and sulphur-containing (sulphides, disulphides, compounds mentioned for the antibacterial properties of coffee
trisulphides) organic substances [66]. They are obtained mostly [87]. The trimethylated alkaloid caffeine significantly inhibited the
from plants by steam distillation [67] or by extraction with super- growth of E. coli O157:H7 at 0.5% concentration [88]. Furthermore,
critical carbon dioxide [68]. Generally, it has been demonstrated tea antioxidant phenolics like epicatechin, catechin, caffeine,
that plants exert better inhibition on Gram-positive, than on Gram- chlorogenic acid, gallic acid, theophylline, theobromine, theaflavin,
negative bacteria [7]. The presence of both antioxidant and anti- gallocatechin, epigallocatechin gallate, catechin gallate, epicatechin
microbial potentials in one molecule renders it even more effective gallate were also demonstrated to feature antimicrobial properties
for food bio-preservation [7]. The antimicrobial features of plant- in case of both Gram-positive and Gram-negative bacteria [89]. In
derived products is generally accompanied by confirmed antioxi- case of arrowroot tea the antimicrobial effect was assigned to cat-
dant capacity (imparted by phenolic acid derivatives such as caffeic echins. Epigallocatechin gallate and epigallocatechin found in
acid, flavonoids and flavone glycosides, coumarins, terpenoids, green tea extract, showed a powerful antimicrobial activity
lignans, polysaccharides), that completes the pharmacological imparted by the galloyl moiety [90]. Green tea exhibited its notable
benefits of such extracts [69e71]. Edible and herbal plants/spices antibacterial activity against a wide spectrum of pathogens that
such as oregano, cinnamon, clove, citral, garlic, coriander, parsley, included resistant strains like methicillin- and ciprofloxacin-
rosemary, lemongrass, sage and vanillin, have been employed alone resistant staphylococci, vancomycin-resistant enterococci and
or combined with other preservation techniques [65,72e74]. ciprofloxacin-resistant Pseudomonas aeruginosa [91].
Ginger, red pepper, black pepper, cumin, chili powder and curry The crude extract of Cinnamomum burmannii had a wide range
powder exerted lower antimicrobial activity [75]. Studies of antibacterial activities against both Gram-positive and Gram-
have been directed, towards assessing the antimicrobial capacity of negative bacteria. Cinnamon stick and its main components ((E)-
several spices against Salmonella and other Enterobacteria. cinnamaldehyde and proanthocyanidins) were characterized by
The reported variation trend of the antibacterial potential significant in vitro antibacterial activity, exhibited against five
was: clove > kaffir lime peels > cumin > cardamom foodborne pathogenic bacteria (Bacillus cereus, Listeria mono-
> coriander > nutmeg > mace > ginger > garlic > holy basil > kaffir cytogenes, Staphylococcus aureus, Escherichia coli, Salmonella ana-
lime leaves [76]. tum or fecal indicator bacteria. The Authors suggested potential
926 A.M. Pisoschi et al. / European Journal of Medicinal Chemistry 143 (2018) 922e935

application of this extract as natural food antimicrobial [92]. I. Phenolic derivatives

The chemical structure of bioactive compounds was found to
correlate with their antimicrobial potency. The antimicrobial effi- 1. Phenols and cynnamic acid derivatives
cacy was influenced by the position of hydroxyl group [17]. The
difference between the antimicrobial efficacy of thymol and
carvacrol has been assigned to the hydroxyl group placed at the
meta position in thymol, as compared to the ortho position in
carvacrol. Alcaraz et al. [93] also pointed towards the importance of
caffeic acid catechol eugenol
the hydroxyl group at position 5 of flavanones and flavones for the
activity against methicillin-resistant Staphylococcus aureus. Ultee
et al. [44] highlighted the importance of the hydroxyl group and of 2. Quinones
delocalized electrons, in the antimicrobial activity of carvacrol,
proved against foodborne pathogens. They showed that Bacillus
cereus was not inhibited due to the absence of hydroxyl groups in
cymene and carvacrol methyl ester. It was stipulated that the
powerful antimicrobial effect of carvacrol was imparted by the -OH
groups together with the delocalized electron system. Phenolic -OH
groups act as proton exchangers, diminishing the pH gradient quinone hypericin
across the cytoplasmic membrane, and causing cell death. Despite
the existence of an -OH group in menthol structure, this hydrox-
3. Flavones and flavonoids
ylated compound lacking the delocalized electron system, did not
exhibit a pronounced antimicrobial activity.
The number of double bonds could also be held accountable for
the antimicrobial strength [94]. To this aim, several compounds
were studied: citronellol, with only one double bond, was found to
be less effective, whereas geraniol and nerol possessing two double flavone catechin chrysin
bonds, exhibited higher antimicrobial activity against bacteria such
as B. cereus, S. aureus and Escherichia coli and yeast Candida albicans. 4. Tannins
The difference in antimicrobial activity of isomeric phenolic com-
pounds, eugenol-isoeugenol, has been ascribed to the position of
the double bond in the aliphatic side chain [94].
Oxygenated terpenes, mainly hydroxylated ones such as thymol
and carvacrol possessed better antibacterial activity as compared to
simple hydrocarbon monoterpenes [6,95]. It was suggested that
hydrocarbons have confined hydrogen bonding capacity, and are
characterized by scarce hydrosolubility that hinders their agar
medium diffusion [96]. The capacity of oxygenated terpenes to
increase membrane permeability causing potassium ions leakage,
explains their activity as antimicrobials. Oxygenated monoterpenes pentagallylglucose procyanidin
were confirmed as main components of Carum carvi L., Verbena
officinalis L. and Majorana hortensis L oils. Anethole was the main 5. Coumarins
compound found in oils made of Pimpinella anisum L. and Foenic-
ulum vulgare Mill. Moreover, C. carvi, V. officinalis and M. hortensis
oils possessed an enhanced antioxidant activity, due to the pres-
ence of carvacrol, anethole and estragol. With respect to the
investigated antibacterial activity, V. officinalis and C. carvi oils were
confirmed to possess the highest efficacy, notably against Bacillus coumarin warfarin 7-hydroxycoumarin
cereus and Pseudomonas aeruginosa. Carvacrol exhibited antibac-
terial activity against Escherichia coli, and thoroughly inhibited
Penicillium citrinum. The above mentioned oils showed no activity
against several tested Lactobacilli strains, while single components
possessed a notable activity [97]. It was also demonstrated that hop II. Terpenoids
extracts containing acids and xanthohumol, another bioactive
compound with eOH groups, could inhibit the Gram-positive
bacteria (with assessed MIC values of 63 and 125 ppm, respec-
tively). Gram-negative bacteria showed resistance in the presence
of the tested hop extracts, as demonstrated in model meat mari-
nade and marinated pork tenderloins. The antimicrobial activity of
hop extracts exerted against L. monocytogenes was diminished in a
fat-containing model meat marinade, but the efficacy of acids
present in this matrix could be enhanced by diminishing pH value
and storage temperatures [98]. menthol capsaicin
The plant-sourced antimicrobials were classiffed on compound
classes [99e101], and we present the structures below.
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III. Alkaloids mainly beef [112,113]. Studies proved the antimicrobial properties
of lactoferrin, against foodborne microorganisms such as Carno-
bacterium, L. monocytogenes, E. coli, and Klebsiella [110,114]. Al-
Nabulsi et al. [115] obtained a reduction of 4 log CFU/ml of Crono-
bacter spp., under the following conditions: 2.5 mg/ml Lf in 0.2%
peptone water within 4 h incubation at 37
C. The effects of lac-
toferrin alone and in combination with nisin improved the micro-
biological quality of meatballs, leading to a notable diminution of
total aerobic bacteria, coliforms, E. coli, total psychrophilic bacteria,
berberine harmane Pseudomonas spp., yeast and mold, respectively [116].
Besides lactoferrin type of antimicrobial peptide, lactoperox-
idase, an enzyme present in milks of cow, ewe, goat, buffalo, pig and
5. Natural antimicrobial agents of animal origin humans exhibited powerful antimicrobial activity over bacteria,
fungi, and viruses [117]. Human milk lactoperoxidase is active
Most antimicrobial systems of animal origin evolved as part of against infections already in the oral cavity and upper gastroin-
host defense mechanisms. A large group of antimicrobial agents of testinal tract [118]. Milk lactoperoxidase preserves microbial qual-
animal origin is represented by antimicrobial peptides like pleu- ity of diary products. Gram-positive bacteria are more resistant to
rocidin, lactoferrin, defensins, and protamine [102]. Such peptides lactoperoxidase-based food preservation than Gram-negative
are considered a viable alternative to antibiotic resistance. More- ones [117].
over, some of these compounds could quickly destroy the cellular Another powerful antimicrobial enzyme found in egg white,
lipid bilayer membranes even of fast-growing microorganisms [15], milk, and blood is lysozyme that is endowed with bacteriolytic role,
and besides their pronounced antibacterial effect against both and has been reported to act efficaciously against food spoilage
Gram-positive and Gram-negative bacteria, they also exhibit anti- microorganisms [15,105]. Lysozyme inhibits the development of
fungal and antiviral activities [103,104]. Clostridium tyrobutyricum spores, as proved by the assay of cheese
Pleurocidin was confirmed to effectively act against Gram- samples [119]. Gram-positive bacteria are the main target of lyso-
positive and Gram-negative bacteria, fighting foodborne microor- zyme, as the cell wall consists of peptidoglycans [15]. Gram-
ganisms such as Vibrio parahemolyticus, L. monocytogenes, E. coli negative bacteria proved resistance to lysozyme, due to the lipo-
O157:H7, Saccharomyces cerevisiae, and Penicillium expansum [55]. polysaccharide layer of their outer membrane that constitutes a
Magnesium and calcium can inhibit the antimicrobial activity of physical barrier. Nevertheless, it has been reported that the sensi-
pleurocidin [51], which may limit the employment of this anti- tivity of Gram-negative bacteria to lysozyme can be promoted in
bacterial peptide in the presence of Mg2þ and Ca2þ. The source of the presence of surfactants and chelating agents such as EDTA,
pleurocidin is the skin mucus membrane of Pleuronectes ameri- because these compounds can initiate membrane disruption
canus [51]. Defensins produced by vertebrates like mammalian [6,120].
phagocytes and epithelial cells of chickens have been confirmed to Some polysaccharides and lipids from animals are also showing
possess antimicrobial potential exerted over bacteria, fungi, and antimicrobial effects. Chitosan, obtained from the exoskeletons of
viruses [15]. Protamine and magainin are peptides that act effica- crustaceans and arthropods, has polycationic structure and is
ciously against bacteria and fungi [15,105,106]. Magainin destroys applied as effective antifungal [121] and antibacterial agent [122].
Gram-positive bacteria and reduces bacterial adhesion to surfaces Chitosan is a deacetylated form of chitin, and represents the second
[106]. Nevertheless, it has been asserted that there are food com- most abundant biopolymer after cellulose. It is constituted of N-
pounds that can reduce the antibacterial activity of protamine. The acetylglucosamine and glucosamine molecules linked by b 1-4
alteration of the electrostatic properties of this peptide would help glycosidic links [123]. Although chitosan exerted antimicrobial ac-
alleviating this shortcoming [7,105]. Milk constitutes another tivities against a series of foodborne microorganisms [124], it acted
source of antimicrobial peptides. Casocidin is the hydrolysis prod- more effectively against Gram-negative than Gram-positive bac-
uct of a S2-casein, by the enzyme chymosin, found in rennet. It teria [123]. The utilization of chitosan in food preservation has been
possesses antibacterial activity, acting against Staphylococcus spp., restricted because of its scarce solubility at neutral and alkaline pH
Sarcina spp., B. subtilis, Diplococcus pneumoniae, and Streptococcus [125]. The shortcoming of solubility limitation of native chitosan
pyogenes [107]. Peptides such as casein A and casein B at 0.05 mM has been solved by N-alkylated disaccharide chitosan derivatives
and 0.22 mM respectively, inhibit the development of pathogenic that act efficiently against E. coli and S. aureus [126]. The S. aureus, L.
strain Enterobacter sakazakii, as confirmed by agar well diffusion monocytogenes, B. cereus, E. coli, Shigella dysenteriae and Salmonella
assay. This points towards the possibility of application of these typhimurium specific antibacterial activity of water-soluble chito-
peptides in milk-based formulas for neonates. Peptides generated san derivatives synthesized by Maillard reactions is suggesting that
from a S2-casein, a S1-casein, and k-casein have proved their these derivatives constitute a good commercial substitute for the
antibacterial potential against E. coli and B. subtilis [108]. In another acid-soluble chitosan [127]. The molecular weight of chitosan
study, the ability of human and bovine milk to inhibit the meta- seems to play a critical role for determining its activity against
bolism of Escherichia coli, was proved by luminescence monitoring S. aureus and E. coli [7,121]. Moreover, chitosan is a water binding
of constructs expressing the luxCDABE genes. Inhibition proved agent, enzyme inhibitor [127], improves membrane permeability of
dependent on both xanthine oxidase activity and on the nitrite plant cells given its polycationic structure [128], functions as bio-
amount, so it was concluded that xanthine oxidase-generated nitric absorbant [129], exerting this latter role versus nutrients of bac-
oxide also acts as antibacterial agent [109]. teria, inhibiting their development. Binding of chitosan to DNA and
Lactoferrin is another antimicrobial peptide that proved its inhibition of mRNA synthesis take place as chitosan penetrates the
ability to act against Gram-positive and Gram-negative bacteria, nucleus of the target microorganism, hampering the synthesis of
fungi, and parasites [6,7,110]. Structurally, lactoferrin is a glyco- mRNA and proteins [130,131].
protein that binds iron, possessing antimicrobial activity not only Chitosan was also used in combination with nanocellulose fibrils
against a large spectrum of bacteria, but also against viruses [111]. and S-nitroso-N-acetyl-d-penicillamine (SNAP) to develop anti-
Lactoferrin is used as antimicrobial in a variety of meat products, bacterial biodegradable composite membranes that were
928 A.M. Pisoschi et al. / European Journal of Medicinal Chemistry 143 (2018) 922e935

ultimately tested for food packaging applications [132]. Antimi- dipping, coating emulsion or direct addition may also be performed
crobial property evaluation of SNAP-incorporated chitosan mem- for natamycin [144].
branes showed an effective zone of inhibition against bacterial
strains of Enterococcus faecalis, Staphylococcus aureus and Listeria
monocytogenes.
Chitosan was also combined with polypropylene (PP) and
propolis, another animal derived antibacterial. Torlak and Sert [133]
have evaluated chitosan coated PP films alone or in combination
with ethanolic extract of propolis (EEP) against foodborne patho-
gens like Bacillus cereus, Cronobacter sakazakii, Escherichia coli natamycin
O157:H7, Listeria monocytogenes, Salmonella typhimurium and
Staphylococcus aureus. The results demonstrated that chitosan Pediocins are synthesized by Pediococcus strains (P. acidilactici
coated films exhibited a broad-spectrum of antibacterial activity. and P. pentosaceus). These bacteriocins are peptides employed for
Incorporation of EPP to coating at 10% (propolis resin/chitosan) the preservation of vegetables and meat products [145]. They are
enhanced the antibacterial activity against all pathogens tested. characterized by thermostability and functionality over a broad pH
range. Pediocins exhibit efficiency against spoilage and pathogenic
organisms, such as L. monocytogenes, E. faecalis, S. aureus, and
Clostridium perfringens [15,113]. The antimicrobial action of ped-
iocin against Oenococcus oeni and other bacteria present in wine
has been investigated and confirmed by Ref. [146].
Reuterin (b-hydroxypropionaldehyde), secreted by Lactobacillus
reuteri possesses a wide spectrum of antimicrobial activity exhibi-
chitosan, with its N-acetyl-D-glucosamine and D-glucosamine units
ted against food pathogens and spoilage organisms. Application of
reuterin from L. reuteri DPC16 results in an important reduction in
Lipids present in food may also inhibit the proliferation of mi- bacterial population such as Gram-positive (L. monocytogenes, S.
croorganisms, preventing the development of pathogenic and aureus) and Gram-negative (S. Typhimurium, E. coli) bacteria [147].
spoilage microorganisms in relation to food. Particularly lipids of The bio-preservation potential of reuterin is complemented by its
animal origin are endowed with antimicrobial activity [134]. Lipids resistance to temperature, presence of proteolytic and lipolytic
present in milk can suppress the growth of Gram-positive and Gram- enzymes, as well as hydrosolubility. It is characterized by stability
negative bacteria and fungi [15,135]. Meanwhile, other fatty acids of over a broad pH range [6,16].
animal origin such as eicosapentaenoic acid and docosahexaenoic
acid could also inhibit Gram-positive and Gram-negative bacteria
[7,135]. It has been assessed that the antimicrobial activity of fatty
acids and monoglycerides is additive, and that their combination
greatly influences the antimicrobial activity of certain milk types, reuterin
while cellular membrane destabilization is the underlying mecha-
nism for microbial cell inactivation. It has been also demonstrated Lactic acid antibacterial action is ascribed to the capacity to cross
that the antimicrobial activity of milk lipids can increase twice by the cellular membranes, resulting in diminished intracellular pH
combining purified fatty acids and monoglycerides [136]. and disruption of the transmembrane proton motive force. This
biopreservation mechanism has also been reported for other
6. Natural preservatives from microbial sources organic acids produced by starter culture bacteria, such as acetic
acid and propionic acid [148]. Studies focused on lactic acid anti-
Nisin represents the only bacteriocin approved in more than 50 bacterial activity showed that this is assigned to undissociated
countries. It is synthesized by Lactoccocus lactis and acts against molecules present at pH 4.0 (40%) and at pH 3.60 (60%) [149]. Acid
Gram-positive and spore-forming bacteria [137e139]. The main dissociation inside the bacterial cell is accompanied by the accu-
targets of this bactericide are Gram-positive foodborne pathogens mulation of toxic anions, stress upon the cell homeostasis, inhibi-
or spoilage bacteria like S. aureus, M. luteus, and B. cereus [140]. tion of metabolic reactions, and depending on the extent of the
Nisin inhibits the growth of yeasts and molds in table olives, when generated effect of division inhibition, even death [150,151]. In case
used in combination with natamycin [141]. of humans, the neutral pH in the large intestine cannot promote the
Nisin presents enhanced activity against Gram-positive bacteria permeabilizing capacity of lactic acid, and it has been stipulated
and controls the development of Clostridium spp in cheese [57,142]. that probiotic lactic acid bacterial strains might inhibit Gram-
The general cationic character of bacteriocins explains pore gen- negative pathogens in the large intestine, and that this action
eration across cellular membranes, and easy interaction with could be due to the synergy of lactic acid and bile salts [152].
Gram-positive bacteria that possess elevated membrane levels of Further cumulative effects could be observed when the anti-
anionic lipids [143]. microbial action of lysozyme against P. aeruginosa was promoted in
The antifungal natamycin is produced by fermentation using the presence of lactic acid and hydrochloric acid. It was also
Streptomyces species. Structurally it is a macrolide polyene, pre- assessed that significant amounts of lipopolysaccharides could be
senting a macrocyclic lactone-ring with conjugated carbonecarbon released by these acids from serovar Typhimurium: namely, the
double bonds. Natamycin acts against almost all foodborne yeasts assay of liberated components by electrophoresis and by fatty acid
and molds but is inactive on bacteria or viruses [144]. Natamycin analysis proved that lactic acid was more active than EDTA or hy-
interacts with ergosterol, hence fungi do not develop resistance. drochloric acid in releasing lipopolysaccharides from the external
Natamycin is primarily applied at surface, on hard cheese and membrane. The antimicrobial activity due to the pH decrease and
salami-type sausages. This antifungal, even when found in dis- the permeabilization of the Gram-negative outer membrane by
solved fraction, migrates with difficulty in food matrices, that lactic acid, is complemented by the enhancement of the effects of
constitutes an advantages over sorbate. Spraying the surface, other antimicrobial compounds [149].
 A.M. Pisoschi et al. / European Journal of Medicinal Chemistry 143 (2018) 922e935 929

7. Natural preservatives from algae and mushrooms Alboofetileh et al. are describing an alginate/clay nano-
composite film enriched with essential oils that proved effective in
The macro - (seaweeds) and microalgae (diatoms) produce suppressing the growth of foodborne pathogens like Listeria mon-
bioactive compounds that combat bacterial invasion in their nat- ocytogenes and spoilage flora in rainbow trout slice [163]. Marjoram
ural ecosystem. Many marine algae derivatives are promising novel essential oil showed the highest inhibitory effect, followed by clove
antimicrobial agents with multiple applicability including phar- and cinnamon.
maceutical and food industry [153]. Carrageenan is an algae derived indigestible polysaccharide for
Much of this research has led to the identification of antimi- humans that when combined with chitosan and allyl isothiocya-
crobials like phlorotannins, fatty acids, polysaccharides, peptides, nate or heat-treated oriental mustard extract, could form an anti-
terpenes, polyacetylenes, sterols, indole alkaloids, aromatic organic bacterial film suitable for active food packaging that significantly
acids, shikimic acid, polyketides, hydroquinones, alcohols, alde- inhibited Campylobacter jejuni growth in case of vacuum-packed
hydes, ketones, halogenated furanones, alkanes and alkenes among raw chicken [164]. Further development of the antimicrobial film
the secondary metabolites of algal classes such as the Phaeophy- was achieved by adding EDTA that increased the potential to reduce
ceae (brown), Rhodophyceae (red), Chlorophyceae (green), Chrys- Salmonella on raw chicken breasts [165].
ophyceae (golden) and Bacillariophyceae (diatoms) [154e156]. Rodríguez-Martínez et al. [166] formulated a new, active
Similarly to fruits, vegetables, herbs and spices, the antimicro- biodegradable film based on polylactic acid, by drying Fucus spiralis
bial activity of algae is complemented by their compounds' anti- seaweed extract and natural sorbic acid. Fucus spiralis was selected
oxidant potential, imparted by the presence of a-tocopherol, because it efficiently inhibited the growth of foodborne bacteria
carotenoids, polyphenols, phycobiliproteins and vitamin C [33]. like Staphylococcus aureus, Bacillus cereus, Bacillus subtilis, Pseudo-
Plaza et al. [157] investigated and proved the antimicrobial monas fluorescens, Escherichia coli, Klebsiella pneumoniae, Aero-
potential of Himanthalia elongata and Synechocystis spp. against monas hydrophila, Vibrio alginolyticus and Vibrio parahaemolyticus,
S. aureus and E. coli. In another study, a more enhanced inhibition when compared to other seaweed algae genera like Ascophyllum,
exerted by seaweed extract of Haligra spp. (50 mg/ml concentra- Ulva, Bifurcaria, and Gracilaria, respectively. Sorbic acid was first
tion) against Gram-positive S. aureus (MTCC 96) was reported, in isolated from mountain ash berries, and has antimicrobial action
comparison with synthetic preservative benzoate (200 mg/ml). mainly against yeasts and molds, but is selective against bacteria.
Authors also obtained a minimal bactericidal activity of Haligra spp. Such experiments are strongly suggesting that the addition of
extract against S. aureus at 5 mg/ml, verified in skimmed milk, whole seaweeds or algal extracts to antibacterial food-films could
showing the potential of this alga to be employed in raw meat, contribute to reducing the volume of traditional preservatives
dairy products, poultry, salads, shrimp, and ham-like foodstuff required. This could reduce production costs, and bring concomi-
[158]. The antifungal and anti-aflatoxinogenic potential of the tant nutritional benefits as algae are also known to contain many
brown alga Cystoseira tamariscifolia has been demonstrated against health-promoting bioactive compounds, too.
yeasts and moulds with pathogenic and toxicogenic activity: Petrovi
c et al. [167] using the fruiting bodies of wild Laetiporus
C. albicans HSZ02 and C. albicans IP4872, Penicillium cyclopium sulphureus (Bull.) Murrill, growing on willow trees from Serbia,
IP1231-80, Aspergillus parasiticus NRRL2999 [159]. prepared methanol extracts that they also tested for antimicrobial
Gupta et al. [160] have studied the antibacterial activity of raw activity - with and without the addition of food additive potassium
and heat processed edible brown seaweeds like Himanthalia elon- disulfite - in vitro against eight bacterial and eight fungal species,
gata, Saccharina latissima and Laminaria digitata against Listeria and in situ in tomato paste against Aspergillus flavus. All the tested
monocytogenes, Salmonella abony, Enterococcus faecalis and Pseu- extracts showed good antimicrobial activity, but the methanol
domonas aeruginosa that are known to cause problems in the food extract containing potassium disulfite featured the best antimi-
industry. The crude Himanthalia elongata extract was more efficient crobial activity in vitro. In situ results indicated the total suppres-
than the standard synthetic preservatives (sodium benzoate, so- sion of A. flavus growth in tomato paste after 15 days of treatment.
dium nitrite) against E. faecalis and P. aeruginosa, while the meth- The antimicrobial potential of the ethanol extracts of Laetiporus
anol extract proved to be more effective against L. monocytogenes. sulphureus (Bull.) Murrill was investigated against Candida albicans
The crude extract of Saccharina latissima and Laminaria digitata ATCC10321, Candida parapsilopsis CBS604, Escherichia coli ATCC8739,
showed similar antimicrobial effects against all four bacteria. Sur- Staphylococcus aureus ATCC6538, Enterococcus faecalis and Staphy-
prisingly, heat treatment significantly reduced the antibacterial lococcus epidermidis ATCC12228. The fruit bodies extract and dried
activity of all crude seaweed extracts. Therefore, the incorporation biomass extract exhibited a broad antimicrobial spectrum, against
of such crude seaweed extracts into raw meat could exert bacterial studied yeast and bacteria strains [168].
inhibition during the uncooked, cold storage phase of the meat The antimicrobial activity of the edible mushrooms extract of
product, while upon heat processing, the crude seaweed extracts non-gilled Aphyllophorales group was tested against pathogenic
will become inactivated. bacteria [6,169]. The extract obtained from these fungi exerted in-
Dussault et al. [161] by applying broth dilution assays, have hibition against both Gram-positive (S. aureus, P. aeruginosa) and
shown that methanol extracts of the brown algae species Padina Gram-negative (P. aeruginosa, E. coli) bacteria. The antimicrobial
and Dictyota, inhibit the growth of Gram-positive foodborne potential of methanolic extract of edible mushrooms from Agaricus
pathogens Listeria monocytogenes, Bacillus cereus and Staphylo- spp. has also been tested, and the results confirmed significant
coccus aureus at low concentrations, while against Gram-negative activity against Gram-positive bacteria, including M. luteus, Micro-
species like E. coli and S. enterica serovar Typhimurium, these ex- coccus flavus, B. subtilis, and B. cereus [170]. The ethanolic extract of
tracts could not exert any growth suppressing effect. Fortunately, Leucoagaricus leucothites found in Turkey has been shown to exhibit
the Padina and Dictyota extracts did not show any toxicity at the strong antimicrobial activity against some foodborne and spoilage
analyzed concentrations, making them good candidates for incor- bacteria [171].
poration into foods prone to Gram-positive bacterial spoilage. Antimicrobial activities of ethanolic extracts of wild edible
Algae-derived carrageenan and alginates can be used for the mushrooms like Armillaria mellea, Meripilus giganteus, Morchella
formulation of edible food coatings, that when combined with costata, Morchella elata, Morchella esculenta var. vulgaris, Morchella
other natural compounds and/or extracts will enlarge their food hortensis, Morchella rotunda, Paxillus involutus, Pleurotus eryngii, and
industrial applications spectra [162]. Pleurotus ostreatus were also evaluated with 11 test
930 A.M. Pisoschi et al. / European Journal of Medicinal Chemistry 143 (2018) 922e935

microorganisms by the agar well diffusion method [172]. characterization of specific bioactive compound profiles of algae
P. ostreatus and M. giganteus were the most active species against and mushrooms, and besides several attempts to evaluate the
the tested bacteria and yeast. antimicrobial potential, fewer attempts were made to use them in
Moreover, 19 Polish wild growing edible mushrooms were order to reduce microbiologic spoilage of foodstuffs.
investigated, and moderate antimicrobial properties were found,
suggesting that either the mushrooms themselves or the extraction
8. Several illustrative applications of natural antimicrobials
methods did not provide adequate yields of bioactive compounds
with antibacterial potential [173].
In Table 1, a synoptic overview of several illustrative applications
Karaman et al. [174] were reporting the assessment of antibac-
of natural antimicrobials from different sources is provided.
terial potential of crude extracts of two edible and two medicinal
lignicolous mushroom species, Meripilus giganteus, Agrocybe
aegerita, Fomes fomentarius and Xylaria polymorpha growing wild in 9. Critical conclusive aspects and prospects
Serbia, and have found that the most noticeable antibacterial effect
was associated with F. fomentarius extract. Antimicrobials originating from natural sources provide new
Recently, several Korean mushrooms were extracted using modalities to ensure microbial safety and increase the shelf-life of
different methods, and the extraction efficiency was tested based foodstuffs [208].
on the antibacterial activity of obtained mushroom extracts against Natural preservatives are not only safe, but constitute a viable
two pathogens, Streptococcus mutans and Pseudomonas aeruginosa alternative to solve the problem of microbial resistance, meeting at
[175]. the same time the requirement for healthy foods [7]. The incor-
It seems therefore likely that algae and mushrooms are prom- poration of natural preservatives to meat, fruits and vegetables, as
ising sources of antibacterial compounds with variable applicability well as to edible packaging leads to shelf-life extention [209].
in food sector. Current research is much focused on Studies devoted to the comparison of plant derivatives with
synthetic antimicrobial compounds and antioxidants confirmed

Table 1
Several illustrative applications of natural antimicrobials.

No. Source of natural antimicrobials Activity Use Reference

1 onion Against gram positive bacteria belonging to genus - food ingredients in processed or cooked foods [176,177]
Bacillus, Micrococcus, Staphylococcus, Streptococcus, as - natural ingredient to delay the deterioration of meat
well as gram negative bacteria, such as Salmonella products, as it is well known that the preservation of
enteridis or some strains of Escherichia coli. palatability, taste, colour and flavour without adding
Onion anti-yeast and anti-fungal activity has been synthetic preservatives is highly demanded by
mainly attributed to the presence of organosulfur- customers
containing compounds which inhibit the growth of - antibrowning agents preventing other vegetables
yeast and fungi such as, Candida albicans, Aspergillus and fruits from the deterioration associated to the
niger, Penicillum cyclopium or Fusarium oxysporum. post-harvest process
2 Grape Against E. coli, Salmonella Typhimurium, and -in ground beef, to reduce the number of pathogens, to [178]
seed extract (ActiVin) and Pine bark extract L. monocytogenes delay lipid oxidation, and color degradation
(Pycnogenol)
3 Microgard(TM) 100, Microgard(TM) 300, Against E. coli, mesophilic bacteria, lactic acid bacteria - acidified chicken meat (sausage batter) [179]
nisin, Alta(TM) 2002, Perlac(TM) 1902,
sodium lactate and essential oil of mustard
4 commercially oil-soluble rosemary extracts Inhibition of lipid oxidation and antimicrobial activity - vacuum-packed chicken frankfurters [180]
VivOX in chicken frankfurters
20 and VivOX 4
5 fresh garlic, garlic powder, garlic oil - antioxidant and antimicrobial effects - meat products preservation [12]
6 rice bran extract - antioxidant activity in raw and cooked catfish - patties of channel catfish (Ictalurus punctatus) [181]
- antimicrobial activities in raw patties during storage
7 rosemary extract - against Campylobacter jejuni - chicken meat [182]
8. - Rosmarinus officinalis L. - antioxidant and antimicrobial effects - packed cooked pork patties [183]
- Melissa officinalis L.
9. chitosan, added individually or in - microbial growth inhibition - fresh pork sausages [124]
combination with rosemary or a- - lipid oxidation delay


tocopherol - shelf life extension during storage at 4 C for 20 days
10. chitosan - antimicrobial effects - vacuum packaged pork sausages [184]
11. chitosan, aqueous extract of ginger, onion - antioxidative and antimicrobial activity - stewed-pork [185]
and garlic
12. raisin juice - reduction in the population of Aspergillus flavus and - liquid bread and bread systems [186]
concentrate Penicillium chrysogenum
13. raisin extracts - inhibition of the growth of ropy-bread-causing Ba- - liquid bread [186]
cillus species - bread systems
- reduction in the B. licheniformis B. subtilis, Aspergillus
flavus and Penicillium chrysogenum populations
14 natamycin - antifungal efficacy - hard/semihard cheese [144]
- meat products: dry sausage
- yogurt
- bakery products
- tomato pure e/paste
- fruit juice
- wine
15. nisin - cheese [187]
 A.M. Pisoschi et al. / European Journal of Medicinal Chemistry 143 (2018) 922e935 931

Table 1 (continued )

No. Source of natural antimicrobials Activity Use Reference

- antimicrobial activity directed primarily against - milk

Gram-positive bacteria and in particular the spore - Bologna sausage
forming one - cooked sausage
- inhibits the germination of Bacillus and Clostridium - pasteurized soups
spores - dipping sauces
- inhibits some non-spore forming bacteria, such as - beer
Staphylococcus, Lactococcus, Lactobacillus, Leuconos- - round steak
toc, Listeria, Pediococcus, and Micrococcus
16. carvacrol - antimicrobial and antioxidant activity - turkey breast ham [188]
17. Cinnamomum zeylanicum essential oil - antimicrobial properties against Escherichia coli - cooked sausage [189]
and Clostridium perfringens bacteria.
18. essential oils of Ocimum basilicum and - antimicrobial activity against Listeria monocytogenes - chicken sausage [190]
Origanum vulgare and Salmonella
19. ethanol extracts from Mistletoe (Viscum - antioxidant activities - ground pork [191]
album L.) -stems - antimicrobial activity - uncooked pork patties
20. gum acacia coating with garlic and - antibacterial and antioxidant agent - meat and fish products [192]
cinnamon
21. natural extracts from tea, grape, chestnut - antioxidant activities - pork patties [193]
and seaweed - antimicrobial activity
- preservative effect in porcine patties stored under
refrigeration
22. hop extracts - antibacterial agent (gram-positive bacteria) - marinated pork tenderloins [98]
23. essential oils Salvia sclarea, Ocimum - bactericidal and fungicidal activities - Iranian white cheese [194]
basilicum
24. ethanolic extract of propolis - reduces microbial population upon beef (S. aureus - minced beef [195]
and E. coli O157:H7
25. essential oil of the endemic Mentha piperita - antimicrobial activity - raw minced beef meat during refrigerated storage at [196]
- limits the lipid oxidation 4
C
26. sumac (Rhus Coraria L.) and barberry - antimicrobial activity - ground sheep meat [197]
(Barberis Vulgaris L.) water extracts - reduces the degree of lipid oxidation
27. taragon (Artemisia dracunculus) esential oil - antibacterial agent- decreased growth rate of - beef burgers [198]
S. aureus
- low antioxidant effect
- flavor enhancer
28. Zataria multiflora essential oils - antimicrobial effects on bacterial growth of Listeria - roast-chicken fillets [199]
monocytogenes
29. ziziphus leaves extract - delay of lipid oxidation and lowering of the total - sausage during cold storage (refrigerated storage for [200]
microbial count in sausage sample 14 days at 2
C)
30. essential oils of basil, bay, black pepper, - antimicrobial effect against Salmonella spp., Listeria - dry cured sausages (chouriço de vinho), but with [201]
cinnamon, cumin, garlic, lemon, nutmeg, monocytogenes and Staphylococcus aureus sensory limitations
orange, oregano, parsley, rosemary,
tarragon and thyme
31. thymol and its main natural source, thyme - antimicrobial effect against E. coli, E. coli O157:H7, - films to preserve perishable food, [202,203]
(Thymus vulgaris L.) and essential oil from P. mirabilis, P. vulgaris, S. typhimurium, S. strawberries and sliced bread
Thymus vulgaris marcescens, Y. enterocolitica, P. fluorescens, P.
putida, Micrococcus spp., S. flava, S. aureus, B.
licheniformis, B. thuringiensis, L. innocua
- antifungal activities
32. polyphenolic extracts from cherry and - antimicrobial activity against Pseudomonas - vacuum-packed pork sausages stored at 4
C [204]
blackcurrant leaves
33. cinnamon, oregano and thyme essential oils - antimicrobial activity against: total coliforms, E.coli - meat and fish [205]
34. Essential oil of Juniperus communis - antimicrobial activity against: Agrobacterium - beverage and meat [66]
tumefaciens, Bacillus subtilis, Esherichia coli and
Pseudomonas flurescens.
35 Thymus serpyllum volatile oil - antifungal activity against: Alternaria - meat, fish and salad [206]
sp. > Aureobasidium sp.> Penicillium sp
36 Citrus oil - inhibitory activity, both in direct oil and vapour - meat, dairy products, fruits, vegetables, [207]
form against a range of both Gram-positive and confectionery
Gram-negative bacteria
37 carvacrol, thymol, eugenol, perillaldehyde, - antimicrobial activity against: Listeria - fresh meat, meat products, fish, milk, dairy products, [21]
cinnamaldehyde and cinnamic acid monocytogenes, Salmonella typhimurium, vegetables, fruit and cooked rice
Escherichia coli O157:H7, Shigella dysenteria,
Bacillus cereus and Staphylococcus aureus

that natural compounds are more active and safer than synthetic acid replication and/or transcription, and protein synthesis.
compounds [9]. The influence of the natural antimicrobial compounds' structure
Natural antimicrobials such as plant-derived components proved crucial for the exhibited preservation potential: the pres-
(polyphenols, essential oils), animal-derived compounds (lyso- ence of -COOH groups involved in protonation/deprotonation
zyme, lactoperoxidase, lactoferrin, antimicrobial peptides or poly- equilibria, the position and number of -OH groups, the conjugated
saccharides such as chitosan), microbial metabolites, algae extracts, double bond systems (such as in phenolics, terpenes or macrolide
act by rupture of the microbial cell membrane, decay of the proton polyenes), the length of fatty acids' carbon chain.
motive force, depletion of ATP pool, that may lead to leakage of It has been proved that natural antimicrobials ensure food
essential biomolecules. Moreover, they can interfere with nucleic safety, as shown by performed trials that included combinations
932 A.M. Pisoschi et al. / European Journal of Medicinal Chemistry 143 (2018) 922e935

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