International Journal of Medical Microbiology 304 (2014) 51–62

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Mini review

Lantibiotics: Promising candidates for future applications in health care Jasmin Dischinger, Shradha Basi Chipalu, Gabriele Bierbaum ∗ Institute of Medical Microbiology, Parasitology and Immunology (IMMIP), University of Bonn, Sigmund-Freud-Straße 25, 53105 Bonn, Germany

a r t i c l e

i n f o

Keywords: Bacteriocins Lanthipeptides Multiresistant pathogens Pharmaceutical applications Alternative therapeutics Lantibiotics

a b s t r a c t The immense potential of bacteria for production of antimicrobials represents an inexhaustible source of new antibiotics. An emerging class of natural products is constituted by ribosomally synthesized and posttranslationally modified peptides (RiPPs). “Lantibiotics” (lanthionine and/or methyl-lanthionine containing antibiotics) belong to the earliest members of this class. The characteristic thioether amino acids are introduced into the precursor peptides by enzyme-mediated posttranslational modifications. The encouraging antimicrobial activity of lantibiotics against multiresistant clinical pathogens, their stability against proteases, heat and oxidation make lantibiotics interesting candidates for novel antimicrobial applications in many areas of the healthcare sector and associated industries. In addition to applications as alternatives to classical antibiotics, lantibiotics can be used as probiotics, prophylactics or additives. Furthermore, the in vitro activity of the lantibiotic modification machinery opens the possibility to generate either improved synthetic lantibiotic peptides or to introduce thioether cross-links into existing therapeutics. © 2013 Elsevier GmbH. All rights reserved.

Introduction Ribosomally synthesized and post-translationally modified peptides (RiPPs) constitute an emerging class of natural products (Arnison et al., 2013). Production of such, structurally very diverse, peptides is a common feature of bacteria, fungi and higher eukaryotes. Bacterial peptides with antimicrobial activity have often been referred to as “bacteriocins”. After the first bacteriocinogenic strain had been identified in 1925, bacteriocin production was described for many Gram-positive and Gram-negative bacteria as well as some archaea (archaeacins) (Gratia, 1925; Tagg et al., 1976; Rodriguez-Valera et al., 1982). According to Klaenhammer (1988), nearly 99% of all bacteria secrete at least one bacteriocin. Indeed, a plethora of new substances has recently been characterized, leading to an enormous gain of knowledge in the field of ribosomally synthesized compounds (for a comprehensive overview and the new classification and nomenclature of this class see Arnison et al., 2013). The term “lantibiotic” was introduced by Schnell et al. (1988) as an abbreviation for “lanthionine containing antibiotic” after identification of the first lantibiotic structural gene. The first compound, nisin, had already been described in 1928 (Rogers, 1928).

∗ Corresponding author. Tel.: +49 228 28719103; fax: +49 228 28714808. E-mail address: [email protected] (G. Bierbaum). 1438-4221/$ – see front matter © 2013 Elsevier GmbH. All rights reserved. http://dx.doi.org/10.1016/j.ijmm.2013.09.003

The group comprises peptides with an elongated or a globular structure as shown in Fig. 1. The early compounds were all isolated from gram-positive producer strains, i.e. firmicutes and actinobacteria, and displayed antibacterial activity. Only when several lanthionine containing peptides without antibacterial activity had been described (Meindl et al., 2010; Goto et al., 2010), one of which was even produced by a cyanobacterium (Li et al., 2010; Tang and van der Donk, 2012), it became obvious that the lantibiotics do not form a distinct family themselves, but instead represent a subgroup of a larger family of lanthipeptides (Arnison et al., 2013).

Gene clusters and regulation Similar to most biosynthetic pathways in bacteria, the genes for lantibiotic biosynthesis are clustered and are designated by the generic locus symbol lan, with a more specific genotypic designation for each lantibiotic member (e.g. nis for nisin). Lantibiotic biosynthetic gene clusters may be found on conjugative transposable elements (e.g. nisin), on plasmids (e.g. lacticin 481) or on the chromosome of the producer (e.g. subtilin) (Chatterjee et al., 2005). The precursor peptide (LanA) consists of an Nterminal leader sequence and the core peptide that is modified after ribosomal synthesis. It is encoded in a biosynthetic gene cluster that typically comprises genes encoding the modification enzymes (lanB and lanC, lanM, labKC, lanL etc.), an exporter (lanT), a protease (lanP) and immunity proteins (lanI, lanH,

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Fig. 1. Structures of different lanthipeptides. (Me)Lan and labionin rings are highlighted by color and residues contributing to the same thioether amino acids are marked in same color. Didehydro amino acids are designated in orange.

lanFEG). The structural gene lanA is often clustered with the genes of the modification enzymes in an operon. Besides this, there is no uniform gene order in the individual gene clusters (Siezen et al., 1996; Willey and van der Donk, 2007; Bierbaum and Sahl, 2009). The biosynthesis of many lantibiotics is regulated by a quorumsensing system consisting of a receptor-histidine kinase (LanK) and its cognate transcriptional response regulator (LanR). The active lantibiotic peptides themselves act as triggering agents and lead to a signal cascade initiated by autophosphorylation of the LanK histidine residue (Kuipers et al., 1995; Schmitz et al., 2006). Subsequently, the phosphate group is transferred to the LanR response regulator that often functions as a transcriptional activator of biosynthesis (van Kraaij et al., 1999; Yonezawa and Kuramitsu, 2005; Willey and van der Donk, 2007). In addition to the more than 95 lanthipeptides described so far (Table 1 ), genome mining has shown that hundreds of further gene clusters still await characterization. Furthermore, these gene clusters are not limited to the firmicutes and actinomycetes but are also found in proteobacteria, chlamydiae, bacteroidetes and cyanobacteria (Marsh et al., 2010; Li et al., 2010).

Lanthipeptide biosynthesis and modification After ribosomal biosynthesis, the serines and threonines of the lanthipeptides are dehydrated to give didehydroalanines (Dha) and didehydrobutyrines (Dhb), respectively. In a subsequent Michael addition, involving the cysteine SH-groups and the double bonds of the dehydro amino acids, the thioether cross-links of lanthionine (Lan) and methyllanthionine (MeLan) are formed. In contrast to previous observations on the stereochemistry of the thioether bridges, an ll- as well as a dl-configuration can occur (Tang and van der Donk, 2012, 2013). A typical lantibiotic contains three to six (methyl-)lanthionines in addition to several Dha and Dhb. Other thioether amino acids comprise the S-aminovinyl-d-cysteine (AviCys) or S-aminovinyl-3-methyl-d-cysteine (AviMeCys) or the labionin (Lab) ring structures (Knerr and van der Donk, 2012). In addition, structural modifications, that are not involved in ring formation such as the hydroxylation of Asp in cinnamycin and the duramycins, hydroxylation of Pro and chlorination of Trp in microbisporicin, and epimerization reactions resulting in d-Ala in lacticin 3147 and lactocin S, occur frequently (Sahl and Bierbaum, 1998). Lantibiotics have been categorized on the basis of their biosynthetic pathways (Willey and van der Donk, 2007; Knerr and

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Table 1 Overview of lanthipeptides (01/2013, adapted from Dischinger et al., 2013). Classification according to Knerr and van der Donk (2012), Residues involved in (Me)Lan bridges are highlighted in colored boxes, whereas subsidiary residues of one thioether aa are marked in same colors. The positions (x) of additional modifications are marked by black, bold letters. Ser and Thr residues that are found to be dehydrated to Dha and Dhb are designated in orange.

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Table 1 (Continued)

SA-FF22)

J. Dischinger et al. / International Journal of Medical Microbiology 304 (2014) 51–62 Table 1 (Continued)

michiganensis subspec.

actagardine)

Lact

3436

pneumoniae

Geobacillus spec.

7aa

55

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Table 1 (Continued)

a

Birri et al. (2012). Garg et al. (2012). Lohans et al. (2012). d Daly et al. (2010). e Fagundes et al. (2011). f Teng et al. (2012). g Wescombe et al. (2012). h Mantovanin et al. (2002) and Mantovani and Russell (2008). i Simone et al. (2013). j Tang and van der Donk (2013). k Sawa et al. (2012). l Krawczyk et al. (2012). m Voeller et al. (2012). n Wang and van der Donk (2012). b c

van der Donk, 2012). In class I lantibiotics (e.g. nisin), the LanB dehydratase converts Ser and Thr to didehydroalanine (Dha) and didehydrobutyrine (Dhb), respectively. Then the LanC cyclase catalyzes the intramolecular addition of Cys thiols to Dha/Dhb to form the lanthionine (Lan) and methyllanthionine (MeLan) cross-links in a zinc dependent manner (Fig. 2). In contrast, in class II lantibiotics (e.g. mersacidin), both the steps are catalyzed by the bifunctional modification enzyme LanM. The C-terminal cyclase domain of LanM has homology to the LanC enzymes, but the N-terminal dehydratase domain does not share similarities with LanB enzymes (Siezen et al., 1996). The LanM enzymes dehydrate hydroxy amino acids via an ATP dependent

phosphorylation (Paul et al., 2007) and their cyclase domains contain three essential zinc binding ligands (Willey and van der Donk, 2007). Moreover, class I peptides are transported by the exporter LanT and the leader is removed by the protease LanP. In contrast, in class II peptides, both, secretion and processing, are mediated by an exporter with an N-terminal protease domain, LanT(P). Class III lanthipeptides (e.g. SapB, labyrinthopeptins) lack antimicrobial activity, but appear to perform morphogenetic and signaling functions for the producer cells. Labyrinthopeptins are characterized by a carbacyclic amino acid called labionin (Meindl et al., 2010). They are posttranslationally processed by the protein

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Fig. 2. Formation of the thioether amino acid (methyl-) lanthionine. Hydroxy amino acids are enzymatically dehydrated to the corresponding didehydro amino acid. Subsequently, in a nucleophilic Michael addition, a Cys derived SH group is connected to the didehydro amino acid resulting in the formation of (methyl-) lanthionine.

kinase-cyclase LabKC, which catalyzes the cyclization of the labionin ring structure in two steps, which include a dehydration via a GTP dependent phosphorylation and subsequently a 2-fold Michael-type addition (Müller et al., 2010). The C-terminal cyclase domain bears limited homology to LanM and LanC and the conserved zinc ligands are missing. Thus, the maturation mechanism of class III lantibiotics differs from that of the other classes (Kodani et al., 2005; Willey et al., 2006). In addition, the gene clusters of class III lanthipeptides possess two LanT-like transporters lacking a dedicated protease domain (Müller et al., 2011; Knerr and van der Donk, 2012). A fourth class of lanthionine synthetases termed LanL was recently discovered from Streptomyces venezuelae (Goto et al., 2010). Lanthipeptides (e.g. venezuelin) modified by this new enzyme-type are classified as class IV lanthipeptides (Knerr and van der Donk, 2012). The C-terminus of LanL also contains a LanC-like cyclase domain including the conserved zinc binding sites found in LanM and LanC. The N-terminus harbors a lyase domain and the central part a serine/threonine kinase domain, both of which align well with the class III synthetases (Goto et al., 2010; Knerr and van der Donk, 2012). The venezuelin gene cluster possesses a LanT and LanH, encoding the ATP binding and membrane permease subunits, respectively, which may be involved in the export (Goto et al., 2010; Knerr and van der Donk, 2012). The gene cluster does not contain a protease involved in leader processing or any immunity-related genes, however the latter function appears to be fulfilled by the exporter LanTH, which is not common for lantibiotics (Goto et al., 2010). The role of the leader peptide has not yet been fully elucidated. The leader appears to be important for the recognition of the precursor peptide by the modification enzymes, e.g. an increase of the dehydration activity, processivity and directionality was shown for the lacticin 481 modifying enzyme (Levengood et al., 2007) – however, in vitro the peptide was also processed when the leader was present in trans or even absent (Levengood et al., 2007). In contrast, the labyrinthopeptin synthetase, LabKC, does not modify its substrate if the leader peptide is not directly attached to the core peptide (Müller et al., 2011). Therefore, the necessity of leader peptides for the modification reactions might differ between the different biosynthetic classes (Knerr and van der Donk, 2012). For those lantibiotics that are processed after export from the cell e.g. nisin, the leader peptide keeps the mature lantibiotic inactive inside the cell, thereby protecting the producer cell. Modes of action and targets The overwhelming majority of lanthipeptides displays an antibacterial activity. With exception of the Neisseriae,

Gram-negatives are generally not affected by lantibiotics due to a protective effect of the outer membrane (OM). Consequently, lantibiotic treatment in concert with an OM destabilizing agent showed an antibiotic effect even against Gram-negative strains (Kordel et al., 1988; Stevens et al., 1991). Some lantibiotics (e.g. nisin Z) can affect selected Gram-negatives such as E. coli, Helicobacter pylori and Neisseria at high concentrations, probably due to either a self-promoted uptake or a lantibiotic-based destabilization of the OM by binding to lipopolysaccharides which is a typical feature of cationic amphiphilic peptides (Nagao et al., 2009). The antibacterial effect generally relies on (a) the inhibition of the cell wall biosynthesis via complex formation and sequestration of the membrane-bound cell wall precursor lipid II and/or (b) the disruption of membrane integrity and pore formation (Fig. 3). Nisin, the most intensively studied lantibiotic, acts by a dual mode of action (MoA) combining both the mechanisms (Wiedemann et al., 2001, 2004). The N-terminal rings (A and B) form a binding pocket, the pyrophosphate cage that allows binding to the pyrophosphate moiety of lipid I/II (Hsu et al., 2004). Complex formation with lipid II prevents transglycosylation by steric hindrance and results in the sequestration of the precursors and, hence, in its abduction from the sites of nascent cell wall biosynthesis (Brötz et al., 1998; Breukink et al., 2003). Moreover, nisin forms membrane spanning and potential-dependent pores consisting of 4 lipid II and 8 nisin molecules (Hasper et al., 2004). Here, lipid II serves as a docking molecule and mediates a ‘targeted’ pore formation (Brötz et al., 1998). The assembly of pores with 2–2.5 nm in diameter (Wiedemann et al., 2004) allows small molecules to leak from the cell, resulting in disruption of the barrier function and, consequently, in dissipation of the membrane potential. Finally, this results in the abrupt arrest of all cellular processes and in cell death (Sahl and Brandis, 1982; Wiedemann et al., 2001). By dissipation of the membrane potential and inhibition of cell wall biosynthesis, nisin and other lanthipeptides are able to inhibit spore outgrowth at the stage of spore germination. This effect also depends on membrane depolarization and lipid II binding (Gut et al., 2011). Other lantibiotics only act by one of these two mechanisms. Due to its elongated structure Pep5 apparently inserts into the membrane, most likely by binding to a so far unknown docking molecule (Sahl and Brandis, 1982; Kordel et al., 1988). In contrast, gallidermin preserves a nisin-like lipid II binding motif, but, since the molecule is shorter than nisin, it is incapable of pore formation in most species and solely acts by inhibition of cell wall biosynthesis (Bonelli et al., 2006). This MoA was also shown for mersacidin-like and lacticin 481-like peptides. These peptides share a conserved TxS/TxEC motif within their essential C-ring (Szekat et al., 2003; Cotter et al., 2006) or A-ring (Boettiger et al.,

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Fig. 3. Overview over the MoA of antimicrobially active lanthipeptides: Almost all lantibiotics act either by inhibition of cell wall biosynthesis by binding and dislocalization of the membrane bound cell wall precursor lipid II and/or disruption of the membrane integrity by pore formation.

2009), respectively, which represents their lipid II binding site (Hsu et al., 2004). Two-peptide lantibiotics may also possess a dual MoA, depending on two peptides that act synergistically (Morgan et al., 2005). While lipid II binding is mediated by the ␣peptide, which is characterized by the lipid II binding motive of mersacidin, the elongated ␤-peptide acts on the membrane by pore formation (Wiedemann et al., 2006). Lipid II complex formation of the ␣-peptide enhances the affinity for the ␤-peptide and allows the ␤-peptide to adopt a transbilayer orientation and to form a pore (Wiedemann et al., 2006). Besides, other biological effects have been discovered for members of the lanthipeptide family. The cinnamycin-like peptides hold antimicrobial activities, but display a different MoA and act by the inhibition of enzymatic functions (Märki et al., 1991). These peptides indirectly inhibit phospholipase A2 by forming a complex with its lipid substrate, phosphatidylethanolamine (PE). Subsequently, this promotes a transbilayer movement of lipids and reorganization of model membranes (Hosoda et al., 1996; Makino et al., 2003). The lanthipeptides SapT and SapB (class III) exhibit a morphogenetic rather than an antibacterial effect; they act as biosurfactants during the emergence of aerial hyphae of streptomycetes (Kodani et al., 2005, 2004). Members of the recently identified labionin-containing lanthipeptides also lack antimicrobial activity (Meindl et al., 2010; Voeller et al., 2012), however, the labyrinthopeptins A1-3 have been demonstrated to numb neuropathic pain in a mouse model (Meindl et al., 2010). For other lanthipeptides e.g. the prochlorosins, bioactivities have not been identified so far (Li et al., 2010).

Lanthipeptides and their applications Today, more than 95 structurally diverse lanthipeptides have been identified and several exhibit intriguing and encouraging bioactivities which make them interesting candidates or lead structures for future applications in many areas. In addition, the lanthipeptides hold many characteristics and chemical properties,

like low molecular weights, thermal and protease stability, lack of toxicity, low tendency to generate resistance and low immunogenicity, which make them suitable for potential applications in different health care associated settings such as in human and veterinary medicine and in biochemical, pharmaceutical, agricultural or food industries. In the following, an overview of possible applications of lanthipeptides currently under investigation is presented. (A) Lanthipeptides in use The first and – so far – only lanthipeptide in commercial use is nisin (Fig. 1). It exhibits an antimicrobial activity against Grampositive bacteria, including agents causing food spoilage like Listeria monocytogenes (Denny et al., 1961) or clostridia, thus it has been employed as a biological food preservative (E234, Nisaplin® ) in processed dairy products, canned fruits and vegetables for more than 50 years. Nisin is also commercially used in animal care products (e.g. Wipe-OUT, ImmuCell) for the prevention of bovine mastitis caused by Staphylococcus aureus or Streptococcus agalactiae (Dawson, 2007). (B) Application as antibiotics Lantibiotics are among the most promising candidates for future antimicrobials due to their capacity to inhibit the growth of clinically significant pathogens including multidrug-resistant staphylococci, streptococci, enterococci and clostridia. In addition, some lantibiotics are also selectively active against a few species of Gram-negative bacteria such as Neisseria and Helicobacter strains. Many lantibiotics bind to the cell wall precursor lipid II, which is also targeted by clinically used antibiotics, but in contrast to the glycopeptides vancomycin and teicoplanin, that complex the d-Ala-d-alanyl group of lipid II, lantibiotics bind to a different site on the target molecule, i.e. the pyrophosphate-sugar moiety (van Heel et al., 2011). Thus, they might overcome the problem of preexisting resistance mechanisms. The potential of lantibiotics to act as antimicrobials is combined with a low tendency to generate resistance, and therefore these compounds are highly attractive for medical applications (van Heel

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et al., 2011; Wilson-Standford and Smith, 2011). Several lantibiotics have been investigated in vitro and in vivo regarding their potential as antimicrobials and a few are currently in preclinical and clinical development. For example, the semisynthetic carboxy-amide derivative of the globular class II lantibiotic deoxy-actagardine B (NVB302, Novacta Biosystems Limited) is currently undergoing a phase I clinical trial as a drug candidate for the treatment of Clostridium difficile infections (www.novactabio.com; Boakes et al., 2010; Li et al., 2012). The lantibiotic derivative NVB333 (Novacta Biosystems Limited) was selected as an injectable drug candidate for the treatment of nosocomial infections caused by Gram-positive pathogens and its promising inhibition spectrum also includes staphylococcal and enterococcal strains resistant to the reserve antibiotics daptomycin and linezolid (www.novactabio.com; Li et al., 2012). Therapy of nosocomial infection is also targeted by the drug candidate microbisporicin (NAI-107, NAICON and Sentinella Pharmaceuticals INC), the most active lantibiotic identified so far (Castiglione et al., 2008). In in vivo experiments, NAI-107 was highly effective in the treatment of infections caused by multiresistant bacteria, such as rat endocarditis caused by MRSA (Jabes et al., 2009). The synthetic lanthipeptide mutacin 1140 (Mu1140-S, Organics) is currently in preclinical development for the treatment of Gram-positive infections and showed interesting in vivo activities against MRSA, vancomycin resistant enterococci, C. difficile, Mycobacterium tuberculosis and Bacillus anthracis (www.organics.com). Nisin exhibits a high efficacy against various relevant human and animal pathogens, making it an effective agent e.g. for the treatment of peptic ulcers (Delves-Broughton et al., 1996). In clinical trials, nisin was highly effective in the treatment of staphylococcal mastitis in lactating dairy cattle (Cao et al., 2007) and in humans (Fernández et al., 2008) and currently, an intramammary infusion product (Mast Out® , ImmuCell) is under development for the treatment of mastitis in lactating cows. Nevertheless, particularly for medical applications, some chemical or pharmacokinetic hurdles often have to be overcome for some lantibiotics with promising biological effects. For nisin, these are its low solubility, lack of peptide stability especially against intestinal enzymes and its low activity at higher pH as well as its tendency to interact with blood components (Boakes and Wadman, 2008). (C) Application as probiotics, prophylactics, preservatives and additives Besides the classical antibiotic use, there are further applications for lantibiotics. Gallidermin and lacticin 3147 are active against the acne causing bacterium Propionibacterium acnes, thus providing the opportunity to use these substances as additives in cosmetics and personal-care products (Zähner et al., 1998; Lawton et al., 2007). In an in vitro colonization experiment, Pep5 and epidermin prevented adhesion of coagulase-negative staphylococci, specifically of S. epidermidis, to catheters coated with silicone (Fontana et al., 2006). The coating of medical devices provides an elegant strategy to reduce catheter-related infections. In line with this, a feasible application as prophylactic against implantate associated infections has been evaluated for gallidermin by the incorporation of the active peptides into prosthetic joint cement (Sandiford et al., 2010). Another prophylactic strategy to combat surgical infections is discussed for mersacidin. In a murine rhinitis model this lantibiotic was shown to be potent in eradicating the nasal colonization by MRSA (Kruszewska et al., 2004). Due to their structures and surface activity, amphiphilic lanthipeptides such as nisin have been discussed to serve as emulsifiers (Bani-Jaber et al., 2000) or as absorption promoters allowing a nasal administration of therapeutics across mucosal membranes (Bower et al., 2001). Lacticin 3147 and the mutacins exert antimicrobial effects on different cariogenic Streptococcus mutants strains and their

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addition to dental applications has been discussed (Suda et al., 2011). The salivaricins have interesting effects against Streptococcus pyogenes strains. Therefore, the salivaricin A producer was supplemented as a probiotic to milk drinks and was demonstrated to persist in the oral cavity. Thus, S. pyogenes infections were prevented by a probiotic bacterial replacement strategy using a strain of the indigenous oral tongue microbiotia that is known for its lantibiotic production (Dierksen et al., 2007). Moreover, chewing gums and lozenges, that include salivaricin-producing S. salivarius strains, have been developed recently and are currently marketed as an oral care product for prophylaxis of dental caries, paradontosis and infection of the oral cavity (BLIS Technologies). (D) Application as other medical therapeutics/pharmaceuticals Some lanthipeptides hold additional bioactivities that are interesting for medical applications. The lanthipeptides of the cinnamycin subgroup were found to influence eukaryotic metabolic functions. Duramycin (Moli1901) stimulates chloride secretion of bronchial epithelia through the activation of calcium-activated chloride channels (Cloutier et al., 1990; Roberts et al., 1991). This effect mainly relies on unspecific changes in the cell membrane rather than on a direct effect on the ion channels (Oliynyk et al., 2010). In a phase II clinical trial, duramycin was proven to be a safe and effective therapeutic for the treatment of cystic fibrosis by inhalation (Grasemann et al., 2007; Grasemann, 2012). Duramycin additionally inhibits the eukaryotic phospholipase A2, which is involved in inflammation by release of inflammation promoting substances e.g. the prostaglandins (Märki et al., 1991). Thus, duramycin might serve as anti-inflammatory or anti-allergy drug. The related ancovenin is a natural inhibitor of the angiotensin I converting enzyme, that is involved in the regulation of cardiac and vascular functions, thereby providing an alternative strategy to treat high blood pressure (Kido et al., 1983). A contraceptive effect due to spermicidal activities has been reported for nisin (Clara et al., 2004). For a few lanthipeptides, antiviral activities have been described in vitro. Cinnamycin is active against retroviruses such as herpes simplex (Naruse et al., 1989), whereas the labyrinthopeptins additionally exhibit a promising anti-dengue-virus effect (Alen et al., 2012). For the latter a dose dependent inhibition of the early step in the replication cycle of the virus was observed. Most likely this is caused by a direct binding to the virus envelope glycoprotein E, which finally blocks the viral infection of targeted cells. In addition, as described above, the labyrinthopeptins hold an unexpected bioactivity to neuropathic pain (Meindl et al., 2010). (E) Applications of the lanthipeptide biosynthesis machinery Usage of the lanthipeptide biosynthesis machinery in in vivo and in vitro bioengineering approaches is a promising technology to design novel antimicrobial compounds. The structure–function relationship of several lantibiotics has been studied by genetic engineering of variant peptides (for a recent review see Ross and Vederas, 2010). Furthermore it has been possible to engineer variant peptides with increased activity, a broader antibacterial spectrum or improved physico-chemical properties (e.g. Appleyard et al., 2009; Field et al., 2012). The promiscuity of the lantibiotic modification enzymes and their ability to display activity in vitro, allow introduction of lantibiotic modifications even into synthetic analogs containing additional unnatural amino acid side chain substitutions. Thus, novel antibiotics could be designed on the basis of the introduction of thioether cross-links into existing therapeutics (Rink et al., 2005; Kluskens et al., 2005). For example, the successful improvement of therapeutically used peptide variants of enkephalin and

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somatostatin by introduction of thioether bridges has already been reported (Ösapay et al., 1997; Rew et al., 2002). To this end, Bosma et al. established an in vivo system that is based on the nisin biosynthesis and transport machinery (Kuipers et al., 2005; Bosma et al., 2011) and introduced didehydro- as well as thioether-amino acids into non-lantibiotic peptides. Using this system they successfully produced lanthionine-bridged variants of the therapeutics vasopressin, enkephalin and angiotensin. Conclusions The potential of lanthipeptides as promising alternatives for traditional antimicrobial therapeutics, as probiotics or preservatives in different areas of the healthcare sector and in associated industries has been discussed for many years. So far, only nisin has been successfully introduced as a preservative into food industry or as a prophylactic in veterinary settings. Although to our knowledge no lantibiotic has reached the approval as an antibacterial therapeutic so far, currently several clinical and preclinical trials explore their high potency as effective pharmaceuticals, mainly as antimicrobial therapeutics or prophylactics. Additionally, the identification of lanthipeptides with intriguing bioactivities other than antimicrobial effects will enlarge their possibilities for applications and it is very likely that investigations in this field will result in the identification of novel MoA and biological effects. Besides, the biosynthesis apparatus itself also holds a high potential for biotechnological use. Its ability to modify peptides in vitro with low selectivity, opens a promising strategy for the generation of improved lanthipeptide analogs or the introduction of thioether cross-links into existing therapeutics. For these very reasons, it is very likely that lanthipeptides or their biochemically modified derivatives will reach the pharmaceutical market. Acknowledgements We gratefully acknowledge the German Research Foundation (DFG, BI 504/9-2 to GB) for funding. Additional support was provided by the BONFOR program of the Medical Faculty, University of Bonn. References Alen, M.F., Neyts, J., Süssmuth, R.D., Brönstrup, M., Schols, D., 2012. Labyrinthopeptins, a new class of lantibiotics, exhibit potent anti-dengue virus activity. In: Twenty-Fifth International Conference on Antiviral Research (ICAR), April 16–19, Sapporo, Japan. Appleyard, A.N., Choi, S., Read, D.M., Lightfoot, A., Boakes, S., Hoffmann, A., Chopra, I., Bierbaum, G., Rudd, B.A., Dawson, M.J., Cortes, J., 2009. Dissecting structural and functional diversity of the lantibiotic mersacidin. Chem. Biol. 29 (16), 490–498. Arnison, P.G., Bibb, M.J., Bierbaum, G., Bowers, A.A., Bugni, T.S., Bulaj, G., Camarero, J.A., Campopiano, D.J., Challis, G.L., Clardy, J., Cotter, P.D., Craik, D.J., Dawson, M., Dittmann, E., Donadio, S., Dorrestein, P.C., Entian, K.D., Fischbach, M.A., Garavelli, J.S., Göransson, U., Gruber, C.W., Haft, D.H., Hemscheidt, T.K., Hertweck, C., Hill, C., Horswill, A.R., Jaspars, M., Kelly, W.L., Klinman, J.P., Kuipers, O.P., Link, A.J., Liu, W., Marahiel, M.A., Mitchell, D.A., Moll, G.N., Moore, B.S., Müller, R., Nair, S.K., Nes, I.F., Norris, G.E., Olivera, B.M., Onaka, H., Patchett, M.L., Piel, J., Reaney, M.J., Rebuffat, S., Ross, R.P., Sahl, H.G., Schmidt, E.W., Selsted, M.E., Severinov, K., Shen, B., Sivonen, K., Smith, L., Stein, T., Süssmuth, R.D., Tagg, J.R., Tang, G.L., Truman, A.W., Vederas, J.C., Walsh, C.T., Walton, J.D., Wenzel, S.C., Willey, J.M., van der Donk, W.A., 2013. Ribosomally synthesized and post-translationally modified peptide natural products: overview and recommendations for a universal nomenclature. Nat. Prod. Rep. 30, 108–160. Bani-Jaber, A., McGuire, J., Ayres, J.W., Daeschel, M.A., 2000. Efficacy of the Antimicrobial Peptide Nisin in Emulsifying Oil in Water. J. Food Sci 65, 502–506. Bierbaum, G., Sahl, H.G., 2009. Lantibiotics: mode of action, biosynthesis and bioengineering. Curr. Pharm. Biotechnol. 10, 2–18. Birri, D.J., Brede, D.A., Nes, I.F., 2012. Salivaricin D, a novel intrinsically trypsinresistant lantibiotic from Streptococcus salivarius 5M6c isolated from a healthy infant. Appl. Environ. Microbiol. 78, 402–410. Boakes, S., Appleyard, A.N., Cortes, J., Dawson, M.J., 2010. Organization of the biosynthetic genes encoding deoxyactagardine B (DAB), a new lantibiotic produced by Actinoplanes liguriae NCIMB41362. J. Antibiot. 63, 351–358.

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