Bacteriocins: Molecules of Fundamental Impact on the ... · while other are related to transpossons, as nisin produced by L. lactis (Ray, 1996). Structural gene location, in other

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Brazilian Archives of Biology and Technology

Vol.48, n. 4 : pp. 559-566, July 2005ISSN 1516-8913 Printed in Brazil BRAZILIAN ARCHIVES OF

BIOLOGY AND TECHNOLOGYA N I N T E R N A T I O N A L J O U R N A L

Bacteriocins: Molecules of Fundamental Impact on theMicrobial Ecology and Potential Food Biopreservatives

Evandro Leite de Souza1*, Clemilson Antonio da Silva2 and Cristina Paiva de Sousa1

1Departamento de Nutrição; Centro de Ciências da Saúde; Universidade Federal da Paraíba; Brasil. 2Programa dePós-graduação em Ciência e Tecnologia de Alimentos; Centro de Tecnologia; Universidade Federal da Paraíba;PB - Brasil

ABSTRACT

Bacteriocins are proteic molecules synthesized for various lineages of Gram-positive and Gram-negative bacteriawhen exposed to stressful conditions. Bacteriocins have been characterized as molecules of high antimicrobialproperty even at low concentrations, provoking the microbial survival inhibition by antibiosis. These substanceshave their synthesis mediated for genetic mechanisms and develop their lethal action on the microbial cell bymultiples mechanisms that can act of isolated or concomitant way culminating with microbial cell kil ling. Thismolecules class presents characteristic of stability to heat, low pH, refrigeration and freezing, and resistance toweak organics solvents, salts and enzymes. On the other hand, they are very sensitive to proteolytic enzymes action.Bacteriocins could appear as potential agents to be applied in food conservation systems in order to providemicrobiologically stable foods.

Key words: Bacteriocins, Antimicrobials, Food Industry, Biopreservation.

HISTORICAL ASPECTS

At the end of the XIX century, Pasteur and Joubertreported the occurrence of antagonisticinteractions among bacteria. These researchersobserved that a bacterial isolate was able tointerfere on the Bacill us antrachis growth (Jack etal., 1995). At the same way, inhibitory actionexerted by a Staphylococcus spp. isolate when ininteraction with Corynebacterium diphyteriae wasalso observed. This discovery led, at that time, theapplication of Staphylococcal isolates as usefulprocedure to be applied in diphtheria treatment andthis therapeutic use was made by steamer form(Florey, 1996). Gátia (1925) first elucidated theinhibition mechanisms occurring in theseprocesses of microbial interactions. It wasobserved that E. coli cells produced in liquidmedium a substance stable to temperature

oscillations and also possessors of inhibitoryactivity on the growth of other taxonomicallysimilar microorganisms. It was, probably, theinitial step for studies involving bacteriocins (Jacket al., 1995). Originally, these substances weredenominated colicins, because most of the studiesobserved their synthesis by E. coli cells. Afterverifying that the synthesis of these molecules wascommon among other bacteria, it was chosen thename bacteriocin to designate them (Jacob et al.,1953). Bacteriocins have been detected in allmajor lineages of Eubacteria and Archaebacteria(Torrebranca et al., 1995).

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CHARACTERIZATION ANDSYNTHESIS

Bacteriocins have been designated as bacterialsubstances with capacity of inhibiting, even in lowconcentrations, the multiplication of other bacteriataxonomically similar (Stainer et al., 1986; Brock,1995). They have formed a heterogeneous groupabout the producing-bacterial species, molecularsize, antibacterial spectrum, stabili ty, physical andchemical properties, and action mode (Davidson

and Hoover, 1993; De Vuyst and Vandame, 1994).They also can be designated as antibiotics bydefinition, even presenting some differences abouttheir applications and clinical effects (Table 01)(Klement et al., 1990; Kuryolowcz, 1991; Davis,1999). Bacteriocins are one of the mostabundant and diversified molecules with antibioticactivity produced by different bacterial generaincluding Gram-positive and Gram-negativespecies (Riley, 1998).

Table 1 -Characteristic aspects of bacteriocins and other conventional antibiotics.Characteristics Bacteriocins Other antibiotics

Application foods clinical

Synthesis ribossomally Secondary metabolism

Activity limited spectrum wide spectrum

Presence of immune cell s in the host present absentAction mode the most through the channel

formation in the cell cytoplasmicmembrane

specific target

Toxicity/other effects in eukaryoticcell s

absent present

Antibiotic designates all substance originated frommicroorganisms, animals, plants or through thesynthetic way that at low concentrations must havethe following properties: i) lethal or inhibitoryactivity against microbial species; ii ) abili ty toprevent the appearance of microbial resistance; ii i)absence of undesirable effects to the host; and iv)chemical stability (Tavares, 1984; Amato Neto etal., 1994; Abrahan et al., 1996). In general way,antibiotics can be defined as agents of greatinterference on the growth and/or microbialactivities (Trabulsi et al., 2002). Substancesrecognized as antibiotic exert their activity bydifferent ways that act on diverse targets in/on themicrobial cell. It includes: i) damaging the cellwall; ii) destabil izing the cytoplasmic membrane;iii) changing the nucleic acid structure; iv)inhibiting the enzymatic action; v) antimetabolicaction; and vi) affecting the acid nucleic synthesis(Pelczar et al., 1980).Looking for nutrients and space for multiplication,some bacteria secrete ribossomally synthesizedpolypeptides (bacteriocins) that cause selectivedeath of competitor microorganisms (Tadashi andSchnneewind, 1998). Surveys have showed thatbacteriocins synthesis is encoded by genes located

in plasmids (for example, Col plasmid in E. colilineages) differently of other antibiotic compoundsthat generally are derivated from secondarymetabolism (Ker and Tate, 1984; Hancock andChapple, 1999; Trabulsi et al., 2002). Geneticdeterminants of many of these molecules havebeen also identified. Some are related withplasmids of different sizes, as pediocinin producedby Pediococcus and lactocin produced byLactococcus lactis. Some are related tochromosomes, as plantaracin A and sakacina 674,while other are related to transpossons, as nisinproduced by L. lactis (Ray, 1996).Structural gene location, in other words, thecodification gene involved in the synthesis ofmany bacteriocins, has been also established.Generally, these structural genes are located in anoperon, which is directly involved in theprocessing and transport of ones through theprokaryotic cytoplasmic membrane (Jack et al.,1995). Bacteriocin molecule is transported throughthe bacterial cell as inactive peptide containing aN-terminal leader and a C-terminal propeptide.The leader portion is removed by specificpeptidases with consequent its activation, beingfollowed for excretion of the active molecule in

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the environment. However, some bacteriocins atpH 5.0 and above remain adsorbed on theproducing-cell surface. These molecules have apositive charge and present the tendency to formaggregates (Klaenhamer, 1993).

MOLECULAR ASPECTS

Many surveys involving bacteriocins study havebeen addressed to understand their generalmolecular characteristics. These molecules presentgenerally proteic nature, varying of low molecularweight polypeptides as those synthesized byphytopahtogenic Corynebacterium species, untilgreat proteic molecules as those synthesized byPseudomonas seringae (Gross and Vidaver, 1979;Stainer et al., 1986; Klement et al., 1990).They are still characterized as cationic andhydrophobic substances, some them presenting adisulfide bridge in their molecular structure. Mostof the ones presents as small molecules, with 50 orless aminoacids. Nisin, most studied bacteriocin,has 35 aminoacids. There are 44 in pediocin AcHproduced by Pediococcus acidilactic, 43 insakacin produced by Lactobacill us sake LB 706,37 in lactacin produced by Lactobacill us lactissubsp. cremosis 9B4 (Daeschel, 1989; Daescheland Ray, 1992; Klaenhammer, 1993). Thesemolecules have stability to heat, low pH,refrigeration and freezing, and also to variousweak organics solvents, salts and enzymes. On theother hand, they are sensitive to proteolyticenzymes (Ray, 1996).

ACTION MODE

Bacteriocins biological action occurs through thespecific receptors located on the target microbialcell surface. After binding with these receptors,various mechanisms act, by isolated orconcomitant way, causing the microbial cellkilli ng (Paker et al., 1989; Daw and Falkiner,1996; Brashears et al., 1998). Bacteriocins arepowerful toxins, often very specific, and usuallyproduced during the exposition of some bacteriallineages to stressful conditions. When released inenvironment cause quick elimination of noimmune or no resistant neighboring microbial cellsto their action (Tadashi and Schnneewind, 1998).

Antagonist action exerted by bacteriocinproducing-bacteria on other bacteria inserted in thesame environment is defined as antibiosis (Hayes,1993). Antibiosis occurs when two or moremicroorganisms present in an environment couldadversely interfere on the growth and survival ofother ones (Ray, 1996). Competition for essentialnutrients, accumulation of D-aminoacids, loweringof oxidation-reduction potential and coagregationmay be involved in antagonism (Schilli nger, 1990;Sinell, 1989). Microbial cell kil ling duebacteriocins action could occur as consequence ofunbalanced cytoplasmic membrane function(affecting energy synthesis and permeabil ity),inhibition of nucleic acid synthesis, interference onthe protein synthesis and changing cell translatormechanism. There are still some bacterial lineagesthat could suffer cell lyse (Daw and Falkiner,1996). Bacteriocin producing-cells are not affectedby action of bacteriocin due to the development ofspecific immunity mediated by a protein (Hancockand Chapple, 1999). Once secreted and activated,the bacteriocin has remarkable property ofdetection and causing death to the competitorbacteria, while provoke li ttle or no damage to itsproducing-cell (Tadashi and Schinneewind, 1998).Bacteriocins are normally effective against Gram-positive bacteria belonging to different genera andclosely related species (Ker and Tate, 1984,Moreno et al., 2000). Nisin end pediocin AcH areexamples of bacteriocins owner of prominentantimicrobial spectrum which are able to exertinhibitory activity on the growth of bacteria suchas Lactobacillus plantarum, Pediococcusacidilactici, Leuconostoc mesenteroides, Listeriamonocytogenes and Micrococcus luteus (Ray,1996).It has been considered as competitive superioritywhen microorganisms dispute ecological niches inthe environment where they are developing theirmetabolic activities (Stockewell et al., 1993).Regarding their narrow action, bacteriocinsprimary role is as intra-specific mediators orpromoters of interactions among microbialpopulations (Cleeveland et al., 2001).

COLICINS

Colicins, bacteriocins produced by E. coli cells,had been focus of several ecological studiesinvolving microorganisms (Paker et al., 1989;Gordon and Riley, 1999). When in stressful

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conditions, such as nutrients depletion oroverpopulation. E. coli cells inserted in a microbialpopulation and able to synthesize colicins areinduced to synthesize them. These molecules arereleased in the environment generally through theproducing-cell lyses. After that, binding betweencolicin and surface receptors located on the targetbacterial cell occurs, followed by transport into thetarget bacterial cell and provoke bacterial death bythree primary mechanisms: i) forming channels inthe plasmatic membrane; ii) degrading DNA; andiii) inhibiting the proteic synthesis (Prado et al.,2000).Recognition and colicins transport are highlyspecific mechanisms able to provoke lethal actiononly on E. coli cells. On the other hand, colicinshave very low inhibitory action on other entericbacteria. Colicin resistance occurrence amongEnterobacteriaceae family representatives suggestthat these molecules act mainly in intra-specificway. Levels of resistance to colicin action amongenteric bacteria are as high as or higher than levelsdetected within of E. coli population (Tadashi andScheennewind, 1998). Colicins producing-cellssynthesize an auto-immune protein that providesprotection or immunity to the bacteriocin producedby themselves. This protein is encoded in anoperon (Figure 1). Once recognized thebacteriocin, a binding between the immune proteinand the colicin C-terminal portion occurs and thisprotect the producing-cell killi ng (Ray, 1996). Themechanism of development of resistanceintermediated by auto-immune protein couldinvolve some alterations in the cellular surfacereceptors. These receptors are used by colicins li kestructures of access for the target cell inside. Thismechanism is recognized as true resistance. Otherkind of development of survival mechanism canoccur due a direct change in the transportprocedure used by bacteriocin across the target cellcytoplasmic membrane and it is results tolerancedevelopment (Cleveland et al, 2001). Only thosemicrobial cells that develop immunity, as well asresistance or tolerance are able to survive underenvironment conditions produced due the colicinaction.On average about 30% of the E. coli naturalpopulation produce colicins. Over 25 kinds ofcolicins have been characterized (Tadashi andSchnneewind, 1998). However, every studiedmicrobial population differs for the combination ofsynthesized colicins, and generally there is one

dominant kind among other ones present.Numerous cells in a microbial population areresistant to one or more produced colicins, with anaverage of 70% being resistant to some colicin,and 30% being resistant to all colicins produced(Gordon and Riley, 1999). In a natural microbialpopulation occurs there a constant flux along timein the relative frequency of E. coli cells which areable to produce colicins, as well as of resistant andsensitive cells to the colicins action (Riley, 1998).

BACTERIOCINS AS POTENTIAL FOODBIOPRESERVATIVES

In the food production it is crucial that suitableactions are taken to guarantee the safety andstabili ty during the food shelf-life. In particular,the current trends adopted by modern consumerand food legislation have made this aim a greatchallenge for the food industry (Brull and Coote,1999). Nowadays, the consumers require foods ofhigh quality, without chemical preservatives, safeand possessing long shelf-life. Concomitantly, thefood legislations have restricted the use of somechemical preservatives in different foods (Brulland Coote, 1999). These have caused manyproblems for the food industry (Piper et al., 1998).Nowadays, there are discussions concerning thenew antimicrobial agents able to be applied infood conservation systems. These agents could beused through the combination of various underlethal treatments and could provide the necessaryprotection to the food against pathogen andspoilage microorganisms (Peck, 1997). Similarly,a new perspective of food conservationemphasizes the application of the named “naturalantimicrobial system”, where could use thesynergistic action of several elements. It includesthe animal, microbial and plant products havingantimicrobial properties, jointly with physicalnature procedure, packaging procedures,manufacture procedures, and the storage foodprocedures. These actions in an associated usecould produce a synergistic effect able topropitiate an unfavorable environment to themicrobial survival (Gould, 1995). This possibilityhas received great emphasis and generates apressure on the food industry to adopt naturalalternatives to achieve its aims related to foodconservation (Brul and Coote, 1999).



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Colicin Immunity Lyse

Figure 1 - Colicins are encoded in an operon. Generally, this operon comprehends threegenes intimately linked: i) a coli cin codifier gene, which functions ascompetitor cell s killer; ii ) a immunity codifier gene, which encoded thesynthesis of a protein able to confer for the producer cell a specific immunityfront the coli cin action; iii ) and a lyses gene, which encoded the synthesis of aprotein able to provoke the producing-cell l yses. It exerts function of releasingthe coli cin in the environment where is inserted the microbial population. Thesegenes are located in an operon, and are encoded by plasmid replication processin E. coli cell (Gordon and Riley, 1999).

Searching new technologies to be applied for foodconservation, the use of substances produced bymicroorganisms deserve prominence. Amongthese substances, bacteriocins deserve specialattention (Daw and Falkiner, 1996). Thesemolecules are included in occurring preservativesclass and biological molecules of low molecularweight subclass (Brul and Coote, 1999).Lactococcus, Streptococcus, Leuconostoc,Pediococcus, Bifidobacterium andPropionibacterium species used in the foodfermentation are admittedly bacteriocins producer.Many of these bacteriocins should have theirdifferent characteristics studied, which isnecessary before their rational use asbiopreservatives (Cleveland et al., 2001).Six general principles must be evaluated for theuse of substances as food additives: i) all proposedadditives must be toxicologically tested andevaluated in all pertinent aspects, includingaccumulative, synergistic and potential effects; ii)only those additives considered safe in theintended level of insertion must be released to use;iii) all food additives must be again evaluatedwhen arisen new information about their use andsafety; iv) food additives must always be kept inconformity as specifications approved by CodexAlimentarius Commission; v) the justification ofthe additives use must be based strongly in therequisites of food safety of different characters ofconsumers, and it also must present aseconomically and technically feasible alternative;vi) the temporary or permanent approval of use ofa food additive must consider the limitation forspecific foods, the purpose, use conditions,decrease of necessary level to reach the desirableeffects and the acceptable daily intake for human,

and still must consider the probable intake ofspecial consumers (Concon, 1980).Some bacteriocins have well established theiraction as potential antimicrobial and also theirpossible applications in food preservation systems.Nisin A already showed effective inhibitoryactivity on the Listeria monocytogenes growth incheese along eight weeks. Enterocin, wheninoculated in ham, pig meat, meat chicken, andsausage, showed inhibitory capacity on the L.monocytogenes growth. Lactocin also hadinhibitory capacity on the same microorganism,when applied in ground meat (Vignolio et al.,1996; Davies, 1999; Aymerich et al., 2000). Thereare numerous applications of nisin as foodpreservative, including shelf-life extension ofdairy products, canned foods, vacuum-packedmeat and cold smoke salmon (Hurst, 1981; Davies,1999; Nilsson et al., 2000).Nisin presents as desirable characters: i) toxicityabsence; ii) naturally produced by Lactococcuslactis; iii) heat stabili ty; iv) storage stabili ty; v)degradation by digestive enzymes; vi) notconferrer undesired taste and flavor to foods; andvii) prominent antimicrobial spectrum againstGram-positive microorganisms (Kominsky, 1999;Fiorentini et al., 2001). But, it is less active toinhibit most of Gram-negative bacteria, yeast andmoulds (Harris et al., 1997).Although bacteriocins antimicrobial role has beenrecognized it is still used a li ttle in foodconservation. Probably, due the absence ofdetailed studies of their particularities. Among themajor bacteriocins, nisin, acidocin, bavaracin,curavaticin, sakacin, although recognized, are notwell characterized. Nisin is the single bacteriocincommercially used as natural agent of foodconservation (biopreservation) and considered safe

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by World Health Organization (WHO) and hasreceived the denomination of GenerallyRecognized as Safe (GRAS) and also by Food andDrug Administration (FDA). Nisin is produced byLactococcus lactis subsp. latis and is used invarious countries (Abee et al., 1994). Diplococcin,lactostrepcin, lactococcins, dricin, lacticin areother bacteriocins also produced by L. lactis(Moreno et al., 2000).Nisin inhibitory action on Gram-positivemicroorganisms occurs through the two stages.First, involves an unspecific interaction betweenthe nisin and the target microbial plasmaticmembrane, which is characterized as reversibleand pH-dependent phenomenon. During thesecond stage, there occur a strong attraction of thenisin with the target citoplasmic membrane, wherelate on channels of diameter 0.1 to 0.2µm areformed. The simultaneous membranedepolarization provokes a quick flux of essentialmolecules (K+ ions, aminoacids, ATP), leading toalterations that culminate with the cellular lyses (Liuand Hansen, 1990).

CONCLUSIONS

The possible use of bacteriocins as foodbiopreservatives could lead to the replacement ofsynthetic chemical preservatives, which have theirantimicrobial action reduced due the continuedappearance of multiresistant microbial lineages.The increasing occurrence of classic and/oremerging food borne diseases and it is possiblyrelated to the indiscriminate use of chemicalspreservatives favoring the selection of microbiallineages more and more resistant, and therefore ofdifficult control. Bacteriocins are agents that couldact on the microbial cell through different wayswhen compared to conventional chemical foodpreservatives, provoking the formation of aninhospitable environment to microbial survival. Inaddition, these molecules present characteristics ofresistance to heat, acidity, low water activity andoscillations of temperature. However, there is thenecessity to develop studies involving theestablishment of the some bacteriocinscharacteristics, such as: i) antimicrobial spectrum;ii) isolation; iii) toxicity; iv) stability; and v)techno-economic viability of their use as controlagents to the growth and microbial survival infoods.

RESUMO

Bacteriocinas são moléculas protéicas sintetizadaspor várias linhagens de bactérias Gram-positivas eGram-negativas quando submetidas a condições destress. São ainda caracterizadas como moléculasde alto poder antimicrobiano mesmo em baixasconcentrações, provocando a inibição dasobrevivência microbiana através de uma ação deantibiose. As bacteriocinas têm seu processo desíntese mediado por mecanismos genéticos, edesenvolvem sua ação letal sobre a célulamicrobiana por intermédio de múltiplosmecanismos que podem agir de forma isolada ouconcomitante culminando com a morte da célulamicrobiana. Estas moléculas apresentamcaracterísticas de estabilidade ao calor, baixo pH,refrigeração, congelamento, resistência a ácidosorgânicos fracos, sais e enzimas, porém são muitosensíveis à enzimas proteolíticas. Assim, asbacteriocinas podem aparecer como potenciaisagentes para serem aplicados em sistemas deconservação de alimentos com objetivo de proveralimentos microbiologicamente estáveis.

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Received: February 02, 2004;Revised: October 01, 2004;

Accepted: May 23, 2005.

Documents

Bacteriocins: Molecules of Fundamental Impact on the ... · while other are related to transpossons, as nisin produced by L. lactis (Ray, 1996). Structural gene location, in other