Friday, 25 July 2014

Chapter # 2 2.1 Enterobacteriaceae:-

2.1 Enterobacteriaceae:-
One of the extremely large family of Gram-negative bacteria is Enterobacteriaceae   that includes many of the more familiar pathogens, such as Salmonella, Escherichia coli, Yersinia pestis, Klebsiella and Shigella, Proteus, Enterobacter, Serratia, and Citrobacter. 
 Members of this family are
1)      Rod shaped
2)       1-5μm in length
3)      Facultative anaerobes
4)      Non spore forming
5)      Few of them are non-motile but some have peritrichious flagella for movement.
These bacteria are able to reduce nitrate to nitrite and capable to ferment sugar to lactic acid and in various other end products. Catalase reaction varies among the bacteria of this family. Most of them are the part of normal gut flora mostly in humans and other animal’s intestine. (Tahoun, 2011)
Most members of Enterobacteriaceae have peritrichious type I fimbriae involved in the adhesion of the bacterial cells to their hosts. Some of them produce endotoxins. Endotoxins reside in the cell cytoplasm and are released when the cell dies and the cell wall disintegrates. Some members of the Enterobacteriaceae produce endotoxins that when released into the bloodstream following cell lysis, cause an inflammatory and vasodilatory response. The most severe form of this is known as endotoxic shock which can be rapidly fatal (Williams, et.al, 2010)
2.2 Escherichia coli:-                                                                                
Escherichia coli was also named as E.coli the German pediatrician Theodore Escherichia was first time identified it from the fecalmaterials of healthy persons and described it in 1885.
Many strains or serotypes of E. coli are found as commensal gut flora that colonizes the gastrointestinal tract of newborns within a few hours of life. The majority of them do not cause any disease unless the host is malnourished, immuno-suppressed or there has been a disturbance in the intestinal barrier. Under these circumstances even commensal E. coli can cause disease (James& Kaper, 1998). Serologically each E. coliisolate can be grouped by its Lipopolysaccharide O-antigen, flagellar H-antigen, capsuleand fimbriae or pilli.
The pathogenic strains include seven distinct categories of E. coli called as virotypethat cause diarrhea.
These can also be referred as pathotypes:                                                
(1) Enterotoxigenic E. coli(ETEC)    
(2) Enteroinvasive E.coli(EIEC)
(3) Enteropathogenic E. coli(EPEC)
(4) Enteroaggregative E. coli (EAEC)
(5) Diffuse Adherent E. coli(DAEC)
(6) Enterohemorrhagic E. coli (EHEC)/ Shiga toxin producing E.coli (STEC)
(7) Opportunistic E.coli
(James& Kaper, 1998)
2.2.1 Enterotoxigenic E. coli (ETEC):-
Enterotoxigenic E. coli is the causative agent of diarrhea in humans, pigs, sheep, goats, cattle, dogs, and horses. ETEC uses fimbrial adhesions (projections from the bacterial cell surface) to bind enterocyte cells in the small intestine. ETEC can produce two proteinaceous enterotoxins:
  • The larger of the two proteins, LT enterotoxin, is similar to cholera toxin in structure and function.
  • The smaller protein, ST enterotoxin causes cGMP accumulation in the target cells and a subsequent secretion of fluid and electrolytes into the intestinal lumen.
ETEC strains are noninvasive, and they do not leave the intestinal lumen. ETEC is the leading bacterial cause of diarrhea in children in the developing world as well as the most common cause of traveler's diarrhea.
2.2.2 Enteroinvasive E.coli(EIEC):-
EPEC also causes diarrhea like ETEC but the molecular mechanisms of colonization and etiology are different. EPEC lack fimbriae ST and LT toxins, but they use an adhesion known as intimin to bind host intestinal cells. This virotype has an array of virulence factors that are similar to those found in Shigella, and may possess a shiga toxin. Adherence to the intestinal mucosa causes a rearrangement of actin in the host cell causing significant deformation. EPEC cells are moderately invasive and elicit an inflammatory response.
2.2.3 Enteropathogenic E. coli (EPEC):-
EIEC infection causes a syndrome that is identical to shigellosiswith profuse diarrhea and high fever found only in humans. The first stage in EPEC pathogenesis involves the initial adherence of bacteria to epithelial cell. EPEC strains typically infect intestine via “attaching and effacing”
2.2.4 Enterohemorrhagic E. coli (EHEC):-
The most notorious member of this virotype is strain O157:H7, which causes bloody diarrhea and no fever. EHEC can cause hemolytic-uremic syndrome and sudden kidney failure. It uses bacterial fimbriae for attachment is moderately invasive and possesses a phage-encoded shiga toxin that can elicit an intense inflammatory response found in humans, cattle, and goats.
2.2.5 Enteroaggregative E.coli (EAEC):-
So named because they have fimbriae which aggregate tissue culture cells, EAEC bind to the intestinal mucosa to cause watery diarrhea without fever. EAEC are noninvasive. They produce a hemolysin and an ST enterotoxin similar to that of ETEC andfound only in humans (Maria, et.al, 2007). Nataro and Kaper first describe the EAEC in culture. Virulence factor associated with EAEC are a heat stable toxin and several aggregative adherence fimbriae (Rosane, et.al, 2013).
2.2.6 Diffuse adherent E. coli (DAEC):-
Diffusely adherent Escherichia coli have been consideredas adiarrhea genic group of E. coli (DEC). They are characterized by the diffuse adherence pattern on cultured epithelial cells HeLa or HEp-2. It cause diarrhea in children and adults both.A key virulence factor in DAEC is the production of adhesions. Three adhesions Afa,Drand F1845 are fimbrial adhesions for the diffuse cells adherence to epithelial tissue. Afa and Dr commonly express together and associated with the urinary tract infection (Rosane, et.al, 2013).
2.2.7 Opportunistic E.coli:-
Are non-pathogenic unless an environmental with in the gastrointestinal tract promotes over population and growth of bacteria. Opportunistic behavior is typical in postsurgical wounds on surgical implants and urinary tract infection.
2.3 Staphylococcus aureus:-
S. aureus is a facultative anaerobicGram-positive coccal bacterium, also known as "golden staph" and Oro staphira. In medical literature the bacteria is often referred to as S. aureus or Staph aureusStaphylococcus should not be confused with the similarly named and medically relevant genusStreptococcusS. aureus appears as grape-like clusters when viewed through a microscope, and has large, round, golden-yellow colonies, often with hemolysis, when grown on blood agar plates. S. aureus reproduces asexually by binary fission. The two daughter cells do not fully separate and remain attached to one another. This is why the cells are observed in clusters (Chambers, 2001).
S. aureus is catalase-positive. Catalase converts hydrogen peroxide to water and oxygen. Catalase-activity tests are sometimes used to distinguish staphylococcifrom enterococci and streptococci. Previously, S. aureus was differentiated from other staphylococci by the coagulase test. However it is now known that not all S. aureus are coagulase-positive and that incorrect species identification can impact effective treatment and control measures

Staphylococcus aureus
Staphylococcus aureus is a bacterium which is the member of the Firmicutes, and is frequently present in the human respiratory tract and also on the skin. Although S. aureus is not always pathogenic, it is a common cause of skin infections (e.g. boils), respiratory disease (e.g. sinusitis), and food poisoning. Disease-associated strains often promote infections by producing potent protein toxins, and expressing cell-surface proteins that bind and inactivate antibodies. The emergence of antibiotic-resistant forms of pathogenic S. aureus (e.g. MRSA) is a worldwide problem in clinical medicine.  Each year, some 500,000 patients in American hospitals contract a staphylococcal infection (Cole, et.al, 2001).     
Staphylococcus was first identified in 1880 in Aberdeen, United Kingdom, by the surgeon Sir Alexander Ogston in pus from a surgical abscess in a knee joint.This name was later appended to Staphylococcus aureus by Rosenbach who was credited by the official system of nomenclature at the time. It is estimated that 20% of the human population are long-term carriers of S. aureus which can be found as part of the normal skin flora and in anterior nares of the nasal passages. S. aureus is the most common species of staphylococcus to cause Staph infections and is a successful pathogen due to a combination of nasal carriage and bacterial immuno-evasive strategies.
S. aureus can cause a range of illnesses, from minor skin infections, such as pimples, impetigo, boils (furuncles), cellulitis folliculitis,carbuncles, scalded skin syndrome, and abscesses,to life-threatening diseases such as, meningitis, osteomyelitis, endocarditis, toxic shock syndrome (TSS), bacteremia, pneumonia and sepsis. Its incidence ranges from skin, soft tissue, respiratory, bone, joint, endovascular to wound infections. It is still one of the five most common causes of nosocomial infections and is often the cause of postsurgical wound infections (Boost, et.al, 2008)
2.4Worldwide discovery of bacteriocins from E.coli:-
Michael Feld garden and Margaret A. Riley in 1997 in their study In this study attempt to characterize more completely the levels of naturally occurring colicin resistance. They present a survey of colicin resistance in 158 E. coli isolates from a variety of hosts and geographic regions of United Kingdom. In addition, they have screened for resistance in 137 isolates of non-E.coli enteric, which are close relatives of E. coli. Their data suggest that resistance levels are high. Similarly high levels of interspecific resistance to colicins are also observed. The frequency of colicin resistance to eighteen colicins is exceptionally high in all four E. coli collections surveyed. On average, 75% of the strains surveyed were resistant to a particular colicin. The average resistance to a particular colicin was the highest for the ECOR collection with a frequency of 91.1% and was the lowest for the Indian collection with a frequency of 67.5%.
            Similarly Riley and Gordon in 1996 do the surveys of over 1000 isolates reveal that, on average, 30% of E. coli produce colicin. Even higher levels of resistance to these same toxins were observed in one survey of E. coli (the ECOR collection; Riley and Gordon 1992). This study suggested that most E. coli are resistant to most colicins. On average, 93% of the isolates were resistant to any one colicin, and 33% were multiple resistant to all the colicins tested (Riley and Gordon 1992)
            David M. Gordon and Claire L. O’Brien in 2005 collect the 266 faecal isolates of Escherichia coli from humans in Australia was assayed for the production bacteriocins and screened using a PCR-based method for the presence of eleven colicins and seven microcins. Eight different colicins were detected and all seven microcins. Of the strains examined, 38 % produced a bacteriocin, 24 % produced a colicin and 20 % produced a microcin. Of the 102 bacteriocin-producing strains, 42 % produced one type of bacteriocin, 41 % produced two, 16 % produced three and one strain was found to produce four different bacteriocins.    
            2.5 Bacteriocin:-
The method to control the pathogenic bacteria is the production of bacteriocin from bacteria.  Both Gram positive and Gram negative bacteria produce bacteriocin (Rowaida,et.al, 2009).    
Historically the term “Bacteriocin” was applied to antibiotic like compounds with specificityprimarily restricted to bacterial strains. This can be thought of as microbial “murder” of onesrelative, but their specificity and chemical composition served to distinguish them from so-called classical antibiotics. (Reeves, 1979).

To go back to the first bacteriocin descriptions amounts to studying the first worksconcerning bacterial antagonism. Such bacterial antagonism was described by the pioneersof microbiology during the last decades of the 19thcentury. At that time, the molecular basisof bacterial inhibition was abstruse, so it was difficult to distinguish antagonism due tobacteriocin from that provoked by other compounds such as antibiotics, organic acids, orhydrogen peroxide, except on the basis of their spectrum of activity, usually narrower thanthat of other ones. (Desriac, 2010).
            The bacteriocins are the proteinaceous substance act as the bactericidal agent that inhibit and often kill the some closely related species of the bacteria.  Bacteriocins inhibit the spoilage of food and also pathogenic bacteria. (Veeranan,et.al, 2009).
Bacteria express produce and utilize these proteins for survival and proliferation of an organism in a mixed population.
The production of these  ribosomally synthesized antimicrobial substance was first described in Escherichia coli which is the Gram negative bacteria (Aylin, et.al, 2001 ) .One of the best known bacteriocin from Gram negative bacteria is colicin produce by the strains of E.coli are large peptide 29-90 kDa , in size. Characteristics of colicins are it involved in cell attachment, translocation and bactericidal activity and attach with the specific receptor of target cells on the outer membrane and in result their activity range would be narrow (Teather, et.al, 1999).
One common event found in Gram negative Bacteriocin production is lethality effect of the producing cells. The bacteriocin is generally produced and released which cause cell death these three events are all directed by the Bacteriocin lysis protein also expressed and produced by the host cell. Gram positive bacteriocins are differing from gram negative in two ways. First Bacteriocin production is not necessarily the lethal event it is for gram negative bacteria also gram positive bacteriocins have evolved Bacteriocin specific regulation.
Bacteriocin also produced by the Gram positive bacteria which are small peptide 3-6 kDa in size in most of cases. They are divided in to two large classes,
Class 1: Lantibiotics bacteriocins.
Class2:Non-lantibiotic bacteriocins.
The post-translational modifications occur in both but in case of lantibiotics additional post translational modifications  are also occur which  giving rise to a variety of unusual amino acid  that include unsaturated amino acid and also a number of other modified amino acid residues. Both classes of peptide antibiotics show the great variety of heterogeneity with respect to amino acid sequence and their effect on the target species. Most of the gram positive bacteria increase the  membrane permeability of cytoplasmic membrane because they are membrane active compound and also demonstrate the broad spectrum of bactericidal activity than colicin due to their activity they do not require the specific cell surface receptor and the absence of outer membrane restrict their access to the cytoplasmic membrane (Teather, et.al, 1999).
Bacteriocins are characterized due to their high level of molecular diversity. Bacteriocin production is a complex high energy demanding process, requiring not only the synthesis of the bacteriocin prepeptide butalso involved in the production of a set of auxiliary proteins that ensure bacteriocin maturation, secretion, regulation and immunity (Ruth,et. al, 2007).

2.5.1 Methods of classification:-
 The alternative methods of classification include method of killing, genetics (large plasmids, small plasmids, chromosomal), molecular weight and chemistry their  (large protein or  polypeptide) and method of production (ribosomal, post ribosomal modifications, non-ribosomal).
The bacteriocins are classified into Class I, Class IIa, and Class III. 
Class I bacteriocins:-
The class I bacteriocins are small peptide inhibitors and include nisin and other lantibiotics.
Class II bacteriocins:-
The class II bacteriocins are small (<10 kDa) heat-stable proteins. This class is subdivided into five sub classes. The class IIa bacteriocins (pediocin-like bacteriocins) are the largest subgroup. The class IIa bacteriocins are used in the food preservation as well as in medical applications because they have broad range of activity. One example of Class IIa bacteriocin is pediocin.
The class IIb bacteriocins require two different peptides for their activity. One example of this class is lactococcin G which permeabilizes cell membranes for monovalent ions such as Na and K, but not for divalents ones.
Class IIc cover the cyclic peptide bacteriocins possesses the N-terminal and C-terminal regions which are covalently linked.
Class IId cover single-peptide bacteriocins which are not post-translated modified. The one of the best example of this group is the aureocin A53which is highly stable. The bacteriocins of this class are stable in highly stable environment.
The most recently proposed subclass is the Class IIe which encompasses those bacteriocins composed by three or four non-pediocin like peptides. The best example is aureocin A70 a four-peptides Bacteriocin and which is highly active against L. monocytogenes with a tremendous biotechnological application (Franz et.al, 2007).
Class III bacteriocins:-
Class III bacteriocins are the large (>10 kDa) protein and heat-labile bacteriocins. This class is subdivided in two subclasses: subclass IIIa or bacteriolysins and subclass IIIb.
Subclass IIIa contain those peptides that kill bacterial cells by degradationand cause cell lysis. The best studied bacteriolysin is lysostaphin, a 27 kDa peptide that hydrolysis several Staphylococcus spp. cell walls especially S. aureus. Subclass IIIb consist of those peptides that do not cause cell lysis and kill the target cells by disrupting the membrane potential.
Class IV bacteriocins:-
Class IV bacteriocins are known as complex bacteriocins containing lipid or carbohydrate moieties. (Franz et.al, 2007)
2.5.2 Medical importance:-
The most of the bacteria used as medicines because they are made by non-pathogenic bacteria which normally colonize the human body. Bacteriocins also serve as cancer treatment.
Bacteriocins were tested as AIDS drugs around 1990 but did not progress beyond in-vitro tests on cell lines.Bacteriocins can target individual bacterial species kill many microbes to the broad spectrum.
2.6 Bacteriocins in human health:-
In addition to bacteriocinogenic probiotics, purified or partially purified bacteriocins also hold great promise with respect to the treatment of target pathogenic bacteria and may ultimately be employed as pharmabiotics and novel alternatives to existing antibiotics. Mersacidin, produced by Bacillus sp. strain HIL Y85, was also active against methicillin-resistant Staphylococcus aureus (MRSA). This bacteriocin was able to completely eradicate MRSA from the nasal epithelium of the mouse, independent of the colonization time and number of inoculations. It has also been shown that a single dose of mutacin B-Ny266, produced by Streptococcus mutans, was 100% protective when administered intraperitoneally to mice previously infected with methicillin-susceptible S. aureus (Mota, et.al, 2005). Finally, it is noteworthy that both lacticin 3147 and thuricin CD produced by Lactococcus lactis DPC3147 andBacillus thuringiensis DPC6431, respectively, exhibited inhibitory activity againstC. difficile.
2.7Colicin:-
Colicins are the macromolecules which are produced by some strains of Escherichia coli and related Enterobacteriaceae family. They occur in protein structures and specified by Col plasmid (Aylin, et. al, 2001). More than 20 colicins have been described in E. coli distinguished by the absence of cross-immunity between the producing strains (Nomura 1963). Colicins are encoded on a diverse group of colicin plasmids (Col plasmids), which usually encode at least two additional colicin-related proteins: an immunity protein, conferring specific immunity to the host and against that colicin, and a lysis protein, involved in lysing the host cell and in releasing colicin into the environment. This group of genes is called a “colicin cluster.” Colicins are abundant in natural populations of E. coli.
The first colicin was identified by Gratia in 1925 as a heat-labile product present in cultures of E.coli. After this variety of colicins produced by different strains of the entire group of bacteria (E. coliShigella, and Citrobacter) were characterized. The name colicin was coined by Gratia and Fredericq in 1946, who demonstrated their protein nature and the specificity of their activity spectra. Colicin kills sensitive cells according to single-hit kinetics and colicin is not active against the producing bacteria due to the presence of a specific antagonist protein called the immunity protein. (Eric, et.al, 2007)
Colicins are the best characterized bacteriocins. Some colicins inhibits
(1) Peptidoglycan synthesis
(2) Lipopolysaccharides O- antigen synthesis, but mostly act as the
(3) Membrane permeabilization which is followed by nuclease activity (Zgur,et .al, 2013)
 Colicins are divided into two groups according totheir cross-resistance patterns.
Group A: A, E1, E2, E3, E9, K, L, N, S4, and X
Group B: B, D, G, H, I, Ia, Ib, M,Q, S and V.
It was later shown that the A and B groups are also distinguished by their mechanism of release from the producing cell. In general, group A colicins are encoded by small plasmids and are released into the medium, whereas group B colicins are encoded by large plasmids and are not secreted. However, some colicins might belong to one group and share homologies with colicins of the other group. (Pilsl,et.al, 1995)
Colicin itself is translocated through the cell envelope rather than any putative constituents that play an intermediate role during its action. The demonstration in 1971 that colicin E3 is a specific RNasethat makes one cut in the 16S rRNA gene significantly changed the model of colicin action. Further on, the endonuclease activity of numerous colicins was demonstrated, with each one specifically cleaving a particular nucleic acid at a precise site. Colicins E2, E7, E8, and E9 cleave DNA (108, 574, 628), and colicins E3, E4, and E6 hydrolyze rRNA while colicins D and E5 cleave tRNA (Eric, et.al, 2007)
In 1963, Nomura demonstrated that the various colicins have different modes of action: colicins E1 and K inhibit all macromolecular synthesis, colicin E2 causes DNA breakdown, and colicin E3 stops protein synthesis (Nourma, 1963).
Although the ecological role of colicins is not clear, several studies reveal that they play a role in bacterial competition and invasion. Under conditions of stress, a small fraction of colicinogenic cells are induced to produce colicin and lysis proteins, an action mediated by the SOS response. The production of lysis protein results in the lysis of the host cell and in the release of colicin. The colicin protein attaches to specific cell surface receptors on nearby E. coli cells and kills the invaded cell by one of four mechanisms, which include DNA and rRNA degradation. If the invaded cells possess the same Co1 plasmid, they will be immune to the effects of the colicin, through a specific interaction between the immunity and colicin proteins (Pugsley, 1984). Colicins of both group A and B target the E.coliby interacting with the specific outer membrane proteins. In group A colicins A, E1 and E9 target the vitamin B12 transporter BtuB (Eric, et.al, 2007).
2.8Microcins:-
The second classes of bacteriocins produced by E. coli, the microcins, are less well understood.Thegene cluster may be chromosomally or plasmid encoded andcomprises two genes: the microcin gene, which encodes thebactericidal protein, and the immunity gene. Cells areinduced to produce the microcin protein under specificconditions, such as iron limitation. The release of microcinsis not a consequence of cell lysis; rather, the microcin isactively secreted from the cell. The export of microcins canbe complex and often involves microcin-specific proteins aswell as basic ‘housekeeping’ proteins (David M. Gordon and Claire L. O’Brien, 2006). Most microcins arethought to bind to surface receptors on target cells involved in iron uptake. The manner in which microcins kill cells isnot generally known, but some disrupt the target cell’smembrane potential. Fourteen microcins have been reported, of which only seven have been isolated and fully characterized(Severinov,et.al, 2007).


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