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Loeza-Lara 2 1 Centro Multidisciplinario de Estudios en Biotecnología, CMEB-FMVZ-UMSNH Morelia, Michoacán 2 Genómica Alimentaria, Universidad de La Ciénega del Estado de Michoacán de Ocampo UCM, Sahuayo, Michoacán, 1,2 México 1. Introduction For over fifty years, people have used antibiotics to treat illnesses caused by pathogens. However, the excessive and inappropriate use of these antibiotics in clinical treatment of humans and animals has increased pathogen resistance to these compounds, turning them into less effective agents. There has also been an increase in the generation of multidrug- resistant pathogens, primarily bacteria and fungi that resist the effects of most currently available antibiotics (Heuer et al., 2006; Field, 2010). Until now, the pharmaceutical industry is facing this problem by looking for new antibiotics or modifying existing ones. However, pathogens have proven to have the ability to quickly develop and disseminate resistance mechanisms, which compromises this strategy, becoming it less effective. This clearly shows the need to develop new biomedical treatments with different action mechanisms from those of conventional antibiotics (Parisien et al., 2008). This problem has led that efforts being made on research and development of new biomedical alternatives, among which antimicrobial peptides (AMPs) are considered one of the most promising options. AMPs are produced by a wide variety of organisms as part of their first line of defense (eukaryotes) or as a competition strategy for nutrients and space (prokaryotes). These molecules are usually short peptides (12-100 amino acid residues); have a positive charge (+2 to +9), although there are also neutral and negatively charged. They are amphipathic and have been isolated from bacteria, plants and animals, including humans; which give us an overview of the enormous structural diversity of these molecules and their different action mechanisms (Murray & Liu, 2008). The continuous discovery of new AMPs groups in diverse organisms has turned these natural antibiotics into the basic elements of a new generation of potential biomedical treatments against infectious diseases in humans and animals. Besides the above, the broad spectrum of biological activities reported for these molecules suggests a potential benefit in cancer treatment, viral and parasitic infections and in the modulation of the immune system, which reinforces the importance of studying these molecules (Mercado et al., 2005; Schweizer, 2009). Biomedical Engineering, Trends, Research and Technologies 276 The contents of this chapter shows the importance of AMPs for living organisms, not only from the antimicrobial point of view, but also in bacterial cell communication processes, immune response modulation in animals and plant defense mechanisms. It also emphasizes on AMPs’ biological and structural diversity, as well as their various action mechanisms and, finally, their possible biotechnological development for the pharmaceutical industry is discussed. 2. AMPs from Gram positive bacteria and their classification During their evolution, bacteria have acquired mechanisms that allow them to have success in competition for nutrients and space in their habitat. These mechanisms include from the enhancement of chemotaxis systems to the acquisition of defense systems such as the production of antimicrobial peptides (AMPs), also called bacteriocins (Riley & Wertz, 2002). AMPs are biologically active molecules that have the ability to inhibit the growth of other members of the same specie or members of different bacterial genres (Cotter et al., 2005b). These molecules are synthesized by the vast majority of bacterial groups; in fact, it has been proposed that 99% of bacteria produce at least one, as they have been found in most examined species, covering Gram positive and Gram negative bacteria and archaea; in addition they are used as an important tool in evolutionary and ecological studies (Klaenhammer, 1988). Also, the successful commercial development of nisin (produced by Lactococcus lactis) and the use of molecular biology and genetic engineering tools in recent years have provoked a resurgence in AMPs studies, particularly in relation to their potential biomedical applications (Cotter et al., 2005a, b; Bierbaum & Sahl, 2009; Field et al., 2010). AMPs from Gram positive bacteria represent a heterogeneous group of chemical molecules; nevertheless only three main categories have been established based on their structural modifications, size, thermostability and action mechanisms (Table 1). Class I (lantibiotics) is constituted by cationic peptides ranging from 19 to 38 amino acid residues, which undergo posttranslational modifications and exert their effect at membrane and cell wall levels. Their posttranslational modifications are diverse; the most important involve dehydration reactions of serine and threonine residues, resulting in the formation of didehydroalanine (Dha) and didehydroaminobutyric acid (Dhb), respectively (Cotter et al., 2005b). The reaction of these amino acids with the thiol group (SH) of a cysteine residue generates a thioether bond producing lanthionine (in the case of Dha) and β-methyl-lanthionine (in the case of Dhb). The formation of these bonds within the peptide generates a series of "globular" structures that are characteristic of lantibiotics. This AMPs class is further divided into subgroups A and B, having nisin as the representative member of subgroup A, while mersacidin, produced by bacteria of the Bacillus genus, is a member of subgroup B (Table 1) (McAuliffe et al., 2001; Cotter et al., 2005a). On the other hand, class II (non lantibiotics) is formed by AMPs constituted by 30 to 60 amino acid residues; they do not contain lanthionine, are thermostable and induce the formation of pores in the membrane of target cells. These peptides in turn are divided into subclasses IIa, IIb, IIc and IId (Table 1). Subclass IIa is the largest and its members posses the amino terminal motif YGNGVXCXXXXVXV (X indicates any amino acid residue) and have one or two disulfide bonds. AMPs from this subclass show specific activity against the bacteria Listeria monocytogenes (Ennahar et al., 2000). Leucocin A from Leuconostoc gelidum is a representative member of this subclass (Hastings et al., 1991). Antimicrobial Peptides: Diversity and Perspectives for Their Biomedical Application 277 Class Subclass Representative AMPs Producing bacteria I Lantibiotic I A Nisin Lactococcus lactis I Lantibiotic I B Mersacidin Bacillus spp. II Non lantibiotic IIa Leucocin A Leuconostoc gelidum II Non lantibiotic IIb Lactococcin G L. lactis II Non lantibiotic IIc AS-48 enterocin Enterococcus faecalis II Non lantibiotic III Proteins IId Lactococcin A Helveticin J L. lactis L. helveticus Table 1. Classification of AMPs found in Gram positive bacteria (Cotter et al., 2005a; Drider et al., 2006) Subclass IIb comprises AMPs that require the combined action of two peptides in order to have activity; these peptides do not show inhibitory activity on an individual basis. Lactococcin G from L. lactis is a representative member of this subclass (Moll et al., 1996). The AMPs that make up subclass IIc posses a cyclic structure as a result of the covalent binding of their carboxyl and amino terminal ends; AS-48 enterocin from Enterococcus faecalis is one of the main representatives of this subclass (Sánchez et al., 2003). Subclass IId is formed by a variable group of linear peptides, among which lactococcin A from L. lactis is found (Holo et al., 1993). Finally, the class III is formed by proteins with molecular masses higher than 30 kDa, the helveticin J from L. helveticus, is an example (Drider et al., 2006). 2.1 Genes involved in AMPs synthesis and expression regulation from Gram positive bacteria The genes encoding AMPs are organized as operons, which could contain several genes involved in the synthesis and regulation. For example, the enterocin A operon of Enterococcus faecium contains the entA gene that codifies for pre-enterocin; in addition, this operon contains the genes that codify for the protein involved in the self-protection of the producing strain (entI), the AMP synthesis induction gene (entF), genes for proteins involved in extracellular transport (entT, D), as well as the genes of proteins related to the AMP synthesis regulation (entK, R) (Nilsen et al., 1998). In the case of lantibiotics, these have additional genes that codify for AMP modification enzymes (McAuliffe et al., 2001). AMPs synthesis regulation is mediated by two signal transduction systems constituted by two or three components. Diverse factors activate these systems, which include: the presence of other competing bacteria (Maldonado et al., 2004), temperature or pH stress (Ennahar et al., 2000) and a mechanism of "quorum sensing" (Kuipers et al., 1998). An Biomedical Engineering, Trends, Research and Technologies 278 interesting example is the three-component system that regulates the synthesis of enterocin A in E. faecium, which is regulated by the mechanism of quorum sensing. This system includes: 1) a histidine kinase (HK), located in the cytoplasmic membrane which detects extracellular signals, and 2) a cytoplasmic response regulator (RR) that mediates an adaptive response, which usually is a change in the gene expression and an induction factor (IF), whose presence is detected by the HK protein (Figure 1, stage 1) (Cotter et al., 2005b). In this case, the system is triggered as a result of an IF excess concentration through a slow accumulation during cell growth, the HK detects this concentration and initiates the signaling cascade that activates the transcription of genes involved in enterocin A synthesis (Figure 1, stages 2 and 3) (Ennahar et al., 2000). Other examples of this type of regulation include several class II members such as sakacin P and A from Lactobacillus sake (Hühne et al., 1996). Moreover, some examples of regulation mediated by two-component systems include numerous lantibiotics, for example, subtilin from Bacillus subtilis and nisin from L. lactis. In these systems AMPs have a dual function, as they have antimicrobial activity and also act as a signal molecule by inducing its own synthesis (not shown) (Kleerebezem, 2004). 2.2 AMPs secretion and self-protection mechanisms from Gram positive bacteria AMPs are synthesized as inactive pre-peptides containing a signal peptide at the N-terminal region (Figure 1, stage 3). This signal keeps the molecule in an inactive form within the producing cell facilitating its interaction with the carrier, and in the case of lantibiotics plays an important role in the pre-peptide recognition by the enzymes that perform posttranslational modifications. The signal peptide may be proteolytically removed during transport of the pre-peptide into the periplasmic space by the same transport proteins (ATP- dependent ABC membrane transporters, which may also contain a proteolytic domain) (Figure 1, stage 4), or by serine-proteases present on the outside of the cell membrane. Thus, the carboxyl terminus is separated from the signal peptide and is released into the extracellular space to produce the biologically active peptide (Figure 1, stage 5) (Ennahar et al., 2000; Cotter et al., 2005b). AMPs producing bacteria possess proteins that protect them from the action of their own peptides. The exact molecular mechanisms by which these proteins confer protection to the producing bacteria are unknown; however, two protection systems have been proposed, which, in some cases act in the same bacteria (Kleerebezem, 2004). The protection can be provided by a specific protein that sequesters and inactivates the AMP, or that binds to the AMP receptor causing a conformational change in its structure making it inaccessible to the AMP (Figure 1, stage 6) (Venema et al., 1994). The second system is constituted by the ABC transport proteins, which in some cases provide the protection mechanism through the expulsion of the membrane-binding AMPs (Otto et al., 1998). 2.3 AMPs spectrum and action mechanisms from Gram positive bacteria In general, the antibacterial action spectrum of AMPs of Gram positive bacteria is restricted to this bacterial group. However, there are several molecules with a wide range of action, inhibiting the growth of Gram positive (McAuliffe et al., 2001) and Gram negative bacteria (Motta et al., 2000), human pathogenic fungi (De Lucca & Walsh, 1999) and viruses (Jenssen et al., 2006). Also, AMPs have activity against various eukaryotic cells, such as human and bovine erythrocytes (Datta et al., 2005). With regard to their antimicrobial activity, AMPs possess essential characteristics in order to carry out the activity, regardless of their target [...]... Shepherins** MBP-1* 28 38 33 0 (linear) 2 Cyclotides 29–31 3 Ib-AMP* 20 2 Family Disulfide bonds Acitivity vs 3–4 6 4 3–4 Bacteria and fungi Bacteria and fungi Bacteria and fungi Bacteria and fungi Gram (+) bacteria and fungi Gram (+) bacteria and fungi Bacteria and fungi Bacteria and fungi Bacteria, viruses and insects Gram (+) bacteria and fungi Table 5 Plant AMPs families (Lay & Anderson, 2005; García-Olmedo... variants by bioengineered (nisin V and nisin T) with enhanced antimicrobial activity against Gram positive pathogens like MRSA, VRE, VISA, Clostridium difficile, L monocytogenes and B cereus (Field et al., 2010)  282 Biomedical Engineering, Trends, Research and Technologies AMPs and producing strain Activity Potential biomedical applications Nisin L lactis Inhibits Gram positive and Gram negative bacteria,... bacteriocin resistance development and associated fitness costs in Listeria monocytogenes Applied and Environmental Microbiology, Vol 68, No 2, 756-764, 00992240 2 98 Biomedical Engineering, Trends, Research and Technologies Guaní-Guerra, E.; Santos-Mendoza, T.; Lugo-Reyes, S & Terán, L (2010) Antimicrobial peptides: General overview and clinical implications in human health and disease Clinical Immunology,... kind of patients and minimize the effects of the infection, that besides rooting out other susceptible P aeruginosa strains, also has an effect on Haemophilus, 286 Biomedical Engineering, Trends, Research and Technologies Neisseria and Campylobacter Regarding the latter, peritonitis treatment in mice has been successful (Scholl & Martin, 20 08; Waite & Curtis, 2009; Williams et al., 20 08) In other studies,... Vol 24, No 4, 7 08- 734, 0265-05 68 Ennahar, S.; Sashihara, T.; Sonomoto, K & Ishizaki, A (2000) Class IIa bacteriocins: biosynthesis, structure and activity FEMS Microbiology Reviews, Vol 24, No 1, 85 106, 01 68- 6445 Enserink, M (1999) Promising antibiotic candidate identified Science, Vol 286 , No 54 48, 2245-2247, 0036 -80 75 Epand, R & Vogel, H (1999) Diversity of antimicrobial peptides and their mechanisms... recently discovered peptide family rich in cysteine, commonly found in the Rubiaceae, Violaceae and Cucurbitaceae families; they present antibacterial and antiviral activities, as well as insecticide properties; besides containing a 288 Biomedical Engineering, Trends, Research and Technologies head-tail cyclic backbone and a knotted arrangement of three conserved disulfide bonds (Daly et al., 2009) LTPs Snakins... Current and potential Gram positive AMPs applications in biomedical therapies AMPs null toxicity to humans and animals and activity directed towards pathogenic bacteria has allowed investigating their potential applications in biomedical therapies In particular, the action mechanisms of these peptides and their activity against pathogens 281 Antimicrobial Peptides: Diversity and Perspectives for Their Biomedical. .. peptides issues for potential clinical use Biodrugs, Vol 17, No 4, 233-240, 1173 -88 04 296 Biomedical Engineering, Trends, Research and Technologies Braun, V.; Pilsl, H & Grob, P (1994) Colicins: structure, modes of action, transfer through membranes and evolution Archives of Microbiology, Vol 161, No 3, 199-206, 030 289 33 Breukink, E.; Wiedemann, I.; Van Kraaij, C.; Kuipers, O.; Sahl, H & Kruijff,... (2002) Biochemical and genetic characterization of Mundticin KS, an antilisterial peptide produced by Enterococcus mundtii NFRI 7393 Applied and Environmental Microbiology, Vol 68, No 8, 383 0- 384 0, 0099-2240 Klaenhammer, T (1 988 ) Bacteriocins of acid lactic bacteria Biochimie, Vol., 70, No 3, 337349, 0300-9 084 Kleerebezem, K (2004) Quorum sensing control of lantibiotic production; nisin and subtilin autoregulate... duramycin B, duramycin C, and cinnamycin as direct inhibitors of phospholipase A2 Biochemical Pharmacology, Vol 42, No 10, 2027-2035, 0006-2952 300 Biomedical Engineering, Trends, Research and Technologies Marr, A.; Gooderham, W & Hancock, R (2006) Antibacterial peptides for therapeutic use: obstacles and realistic outlook Current Opinion in Pharmacology, Vol 6, No 5, 4 684 72, 1471- 489 2 Masaki, H & Ogawa, . difficile, L. monocytogenes and B. cereus (Field et al., 2010). Biomedical Engineering, Trends, Research and Technologies 282 AMPs and producing strain Activity Potential biomedical applications. stress (Ennahar et al., 2000) and a mechanism of "quorum sensing" (Kuipers et al., 19 98) . An Biomedical Engineering, Trends, Research and Technologies 2 78 interesting example is the. responsible for the translocation of the peptide to the Biomedical Engineering, Trends, Research and Technologies 284 AMPs and producing bacteria Group Main features Colicin Escherichia