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

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International Journal of Medical Microbiology

journal homepage: www.elsevier.com/locate/ijmm

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 a b s t r a c t

Keywords: The immense potential of bacteria for production of antimicrobials represents an inexhaustible source
Bacteriocins of new antibiotics. An emerging class of natural products is constituted by ribosomally synthesized and
Lanthipeptides posttranslationally modified peptides (RiPPs). “Lantibiotics” (lanthionine and/or methyl-lanthionine con-
Multiresistant pathogens
taining antibiotics) belong to the earliest members of this class. The characteristic thioether amino acids
Pharmaceutical applications
are introduced into the precursor peptides by enzyme-mediated posttranslational modifications. The
Alternative therapeutics
Lantibiotics 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 gen-
erate either improved synthetic lantibiotic peptides or to introduce thioether cross-links into existing
therapeutics.
© 2013 Elsevier GmbH. All rights reserved.

Introduction The group comprises peptides with an elongated or a globular

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 eukary-
otes. 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, lead-
ing 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 com-
pound, nisin, had already been described in 1928 (Rogers, 1928).
∗ Corresponding author. Tel.: +49 228 28719103; fax: +49 228 28714808.
E-mail address: bierbaum@microbiology-bonn.de (G. Bierbaum).
structure as shown in Fig. 1. The early compounds were all isolated
from gram-positive producer strains, i.e. firmicutes and acti-
nobacteria, 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 desig-
nation for each lantibiotic member (e.g. nis for nisin). Lantibiotic
biosynthetic gene clusters may be found on conjugative trans-
posable 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 N-
terminal 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 modifica-
tion enzymes (lanB and lanC, lanM, labKC, lanL etc.), an exporter
(lanT), a protease (lanP) and immunity proteins (lanI, lanH,

1438-4221/$ – see front matter © 2013 Elsevier GmbH. All rights reserved.
http://dx.doi.org/10.1016/j.ijmm.2013.09.003
52 J. Dischinger et al. / International Journal of Medical Microbiology 304 (2014) 51–62
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 quorum-
sensing 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 tran-
scriptional 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 clus-
ters are not limited to the firmicutes and actinomycetes but are also
found in proteobacteria, chlamydiae, bacteroidetes and cyanobac-
teria (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 lanthion-
ine (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 for-
mation such as the hydroxylation of Asp in cinnamycin and the
duramycins, hydroxylation of Pro and chlorination of Trp in micro-
bisporicin, 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 biosyn-
thetic pathways (Willey and van der Donk, 2007; Knerr and
 J. Dischinger et al. / International Journal of Medical Microbiology 304 (2014) 51–62 53

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

Table 1 (Continued)

SA-FF22)
 J. Dischinger et al. / International Journal of Medical Microbiology 304 (2014) 51–62 55

Table 1 (Continued)

michiganensis subspec.

actagardine)

Lact

3436

pneumoniae

Geobacillus spec.

7aa
56 J. Dischinger et al. / International Journal of Medical Microbiology 304 (2014) 51–62

Table 1 (Continued)

a
Birri et al. (2012).
b
Garg et al. (2012).
c
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).

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 sim-
ilarities 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
 J. Dischinger et al. / International Journal of Medical Microbiology 304 (2014) 51–62
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 con-
served 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 eluci-
dated. 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 directional-
ity 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 lan-
tibiotic 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,
57
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, Heli-
cobacter pylori and Neisseria at high concentrations, probably due
to either a self-promoted uptake or a lantibiotic-based destabiliza-
tion 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 sequestra-
tion 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 bind-
ing 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 hin-
drance and results in the sequestration of the precursors and,
hence, in its abduction from the sites of nascent cell wall biosyn-
thesis (Brötz et al., 1998; Breukink et al., 2003). Moreover, nisin
forms membrane spanning and potential-dependent pores con-
sisting of 4 lipid II and 8 nisin molecules (Hasper et al., 2004).
Here, lipid II serves as a docking molecule and mediates a ‘tar-
geted’ 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 bar-
rier function and, consequently, in dissipation of the membrane
potential. Finally, this results in the abrupt arrest of all cellular pro-
cesses 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 con-
trast, 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.,
58 J. Dischinger et al. / International Journal of Medical Microbiology 304 (2014) 51–62
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 mem-
brane 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 trans-
bilayer orientation and to form a pore (Wiedemann et al.,
2006).
Besides, other biological effects have been discovered for mem-
bers 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 antibacte-
rial 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 lan-
thipeptides 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 immuno-
genicity, which make them suitable for potential applications in
different health care associated settings such as in human and vet-
erinary medicine and in biochemical, pharmaceutical, agricultural
or food industries. In the following, an overview of possible applica-
tions 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 Gram-
positive 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 pre-
existing 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
 J. Dischinger et al. / International Journal of Medical Microbiology 304 (2014) 51–62
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 clini-
cal 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 Clostrid-
ium 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 treat-
ment of nosocomial infections caused by Gram-positive pathogens
and its promising inhibition spectrum also includes staphylococcal
and enterococcal strains resistant to the reserve antibiotics dapto-
mycin 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 infec-
tions and showed interesting in vivo activities against MRSA,
vancomycin resistant enterococci, C. difficile, Mycobacterium tuber-
culosis 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 treat-
ment 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 treat-
ment of mastitis in lactating cows.
Nevertheless, particularly for medical applications, some chem-
ical 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 pre-
vented 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 infec-
tions 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 lantibi-
otic was shown to be potent in eradicating the nasal colonization
by MRSA (Kruszewska et al., 2004). Due to their structures and sur-
face 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 therapeu-
tics across mucosal membranes (Bower et al., 2001).
Lacticin 3147 and the mutacins exert antimicrobial effects
on different cariogenic Streptococcus mutants strains and their
59
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 supple-
mented as a probiotic to milk drinks and was demonstrated to
persist in the oral cavity. Thus, S. pyogenes infections were pre-
vented by a probiotic bacterial replacement strategy using a strain
of the indigenous oral tongue microbiotia that is known for its lan-
tibiotic 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 cin-
namycin 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 promot-
ing 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 addi-
tionally 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 addi-
tion, 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 introduc-
tion of thioether cross-links into existing therapeutics (Rink et al.,
2005; Kluskens et al., 2005). For example, the successful improve-
ment of therapeutically used peptide variants of enkephalin and
60 J. Dischinger et al. / International Journal of Medical Microbiology 304 (2014) 51–62
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 biosyn-
thesis 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 vaso-
pressin, enkephalin and angiotensin.
Conclusions
The potential of lanthipeptides as promising alternatives for tra-
ditional antimicrobial therapeutics, as probiotics or preservatives
in different areas of the healthcare sector and in associated indus-
tries 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 antimicro-
bial effects will enlarge their possibilities for applications and it is
very likely that investigations in this field will result in the identifi-
cation 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 lanthipep-
tides 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 pro-
vided 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., Tru-
man, 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 modi-
fied 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 Antimi-
crobial 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 bio-
engineering. Curr. Pharm. Biotechnol. 10, 2–18.
Birri, D.J., Brede, D.A., Nes, I.F., 2012. Salivaricin D, a novel intrinsically trypsin-
resistant 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 biosyn-
thetic genes encoding deoxyactagardine B (DAB), a new lantibiotic produced by
Actinoplanes liguriae NCIMB41362. J. Antibiot. 63, 351–358.
Boakes, S., Wadman, S., 2008. The therapeutic potential of lantibiotics. Innovation in
Pharmaceutical Technology: Drug Discovery and Development (IPT 27), 22–25.
Boettiger, T., Schneider, T., Martinez, B., Sahl, H.G., Wiedemann, I., 2009. Influence
of Ca2+ ions on the activity of lantibiotics containing a mersacidin-like lipid II
binding motif. Appl. Environ. Microbiol. 75, 4427–4434.
Bonelli, R.R., Schneider, T., Sahl, H.G., Wiedemann, I., 2006. Insights into in vivo
activities of lantibiotics from gallidermin and epidermin mode-of-action studies.
Antimicrob. Agents Chemother. 50, 1449–1457.
Bosma, T., Kuipers, A., Bulten, E., de Vries, L., Rink, R., Moll, G.N., 2011. Bacterial
display and screening of posttranslationally thioether-stabilized peptides. Appl.
Environ. Microbiol. 7, 6794–6801.
Bower, C.K., Bothwell, M.K., McGuire, J., 2001. Lantibiotics as surface active agents
for biomedical applications. Colloids Surf. B Biointerfaces 22, 259–265.
Breukink, E., van Heusden, H.E., Vollmerhaus, P.J., Swiezewska, E., Brunner, L.,
Walker, S., Heck, A.J., de Kruijff, B., 2003. Lipid II is an intrinsic component of the
pore induced by nisin in bacterial membranes. Biol. Chem. 278, 19898–19903.
Broetz, H., Josten, M., Wiedemann, I., Schneider, U., Götz, F., Bierbaum, G., Sahl, H.G.,
1998. Role of lipid-bound peptidoglycan precursors in the formation of pores by
nisin epidermin and other lantibiotics. Mol. Microbiol. 30, 317–327.
Cao, L.T., Wu, J.Q., Xie, F., Hu, S.H., Mo, Y., 2007. Efficacy of nisin in treatment of
clinical mastitis in lactating dairy cows. J. Dairy Sci. 90, 3980–3985.
Castiglione, Lazzarini, F., Carrano, A., Corti, L., Ciciliato, E., Gastaldo, I., Candiani, L.,
Losi, P., Marinelli, D., Selva, F., Parenti, E., 2008. Determining the structure and
mode of action of microbisporicin a potent lantibiotic active against multiresis-
tant pathogens. Chem. Biol. 15, 22–31.
Chatterjee, C., Paul, M., Xie, L., van der Donk, W.A., 2005. Biosynthesis and mode of
action of lantibiotics. Chem. Rev. 105, 633–684.
Clara, A., Gupta, S.M., Reddy, K.V.R., 2004. Spermicidal activity of Nisin: in vitro and
in vitro studies. Contraception 69, 333–342.
Cloutier, M.M., Guernsey, L., Mattes, P., Koeppen, B., 1990. Duramycin enhances
chloride secretion in airway epithelium. Am. J. Physiol. 259, 450–454.
Cotter, P.D., Deegan, L.H., Lawton, E.M., Draper, L.A., O’Connor, P.M., Hill, C., Ross,
R.P., 2006. Complete alanine scanning of the two-component lantibiotic lac-
ticin 3147: generating a blueprint for rational drug design. Mol. Microbiol. 62,
735–747.
Daly, K.M., Upton, M., Sandiford, S.K., Draper, L.A., Wescombe, P.A., Jack, R.W.,
O’Connor, P.M., Rossney, A., Götz, F., Hill, C., Cotter, P.D., Ross, R.P., Tagg, J.R.,
2010. Production of the Bsa lantibiotic by community-acquired Staphylococcus
aureus strains. J. Bacteriol. 192, 1131–1142.
Delves-Broughton, J., Blackburn, P., Evans, R.J., Hugenholtz, J., 1996. Applications of
the bacteriocin, nisin. Antonie Van Leeuwenhoek 69, 193–202.
Denny, C.B., Sharpe, L.E., Bohrer, C.W., 1961. Effects of tylosin and nisin on canned
food spoilage bacteria. Appl. Microbiol. 9, 108–110.
Dierksen, K.P., Moore, C.J., Inglis, M., Wescombe, P.A., Tagg, J.R., 2007. The effect
of ingestion of milk supplemented with salivaricin A-producing Streptococcus
salivarius on the bacteriocin-like inhibitory activity of streptococcal populations
on the tongue. FEMS Microbiol. Ecol. 59, 584–591.
Dischinger, J., Wiedemann, I., Bierbaum, G., Sahl, H.G., 2013. Lantibiotics. In: Abba
Kastin, J. (Ed.), Handbook of Biologically Active Peptides. , second ed. Academic
Press Incorporation, Elsevier, San Diego, USA, pp. 119–128.
Fagundes, P., Ceotto, H., Potter, A., Vasconcelos de, P., Maria, A., Brede, D., Nes, I.F.,
Bastos, M., 2011. Hyicin 3682, a bioactive peptide produced by Staphylococcus
hyicus 3682 with potential applications for food preservation. Res. Microbiol.
162, 1052–1059.
Fernandez, L., Delgado, S., Herrero, H., Maldonado, A., Rodriguez, J.M., 2008. The
bacteriocin nisin, an effective agent for the treatment of staphylococcal mastitis
during lactation. J. Hum. Lact. 24, 311–316.
Field, D., Begley, M., O’Connor, P.M., Daly, K.M., Hugenholtz, F., Cotter, P.D., Hill,
C., Ross, R.P., 2012. Bioengineered nisin A derivatives with enhanced activity
against both Grampositive and Gram- negative pathogens. PLoS ONE 7, e46884.
Fontana, M.B., de Bastos, M.C., Brandelli, A., 2006. Bacteriocins Pep5 and epider-
min inhibit Staphylococcus epidermidis adhesion to catheters. Curr. Microbiol.
52, 350–353.
Garg, N., Tang, W., Goto, Y., Nair, S.K., van der Donk, W.A., 2012. Lantibiotics from
Geobacillus thermodenitrificans. PNAS 109, 5241–5246.
Goto, Y., Li, B., Claesen, J., Shi, Y., Bibb, M.J., van der Donk, W.A., 2010. Discovery
of unique lanthionine synthetases reveals new mechanistic and evolutionary
insights. PLoS Biol. 8, e1000339.
Grasemann, H., 2012. New developments in pharmaceutical treatments for cystic
fibrosis. Curr. Pharm. Des. 18, 613.
Grasemann, H., Stehling, F., Brunar, H., Widmann, R., Laliberte, T.W., Molina, L.,
Döring, G., Ratjen, F., 2007. Inhalation of Moli1901 in patients with cystic fibrosis.
Chest 131, 1461–1466.
Gratia, A., 1925. Sur un remarquable example d’antagonisme entre deux souches de
colibacille. Comp. Rend. Soc. Biol 93, 1040–1041.
Gut, I.M., Blanke, S.R., van der Donk, W.A., 2011. Mechanism of inhibition of Bacillus
anthracis spore outgrowth by the lantibiotic nisin. ACS Chem. Biol. 6, 744–752.
Hasper, H.E., Kruijff, B., de Breukink, E., 2004. Assembly and stability of nisin-lipid II
pores. Biochemistry 43, 11567–11575.
Hosoda, K., Ohya, M., Kohno, T., Maeda, T., Endo, S., Wakamatsu, K., 1996. Structure
determination of an immunopotentiator peptide, cinnamycin, complexed with
lysophosphatidylethanolamine by 1H-NMR1. J. Biochem. 119, 226–230.
Hsu, S.T., Breukink, E., Tischenko, E., Lutters, M.A., de Kruijff, B., Kaptein, R., Bonvin,
A.M., van Nuland, N.A., 2004. The nisin-lipid II complex reveals a pyrophosphate
cage that provides a blueprint for novel antibiotics. Nat. Struct. Mol. Biol. 11,
963–967.
 J. Dischinger et al. / International Journal of Medical Microbiology 304 (2014) 51–62
Jabes, D., Brunati, C., Guglierame, S., Donadio, S., 2009. In vitro antibacterial profile of
the new lantibiotic NAI-107. In: 49th Annual Meeting of Interscience Conference
on Antimicrobial Agents and Chemotherapy, September 12–15, San Francisco.
Kido, Y., Hamakado, T., Yoshida, T., Anno, M., Motoki, Y., Wakamiya, T., Shiba,
T., 1983. Isolation and characterization of ancovenin, a new inhibitor of
angiotensin I converting enzyme, produced by actinomycetes. J. Antibiot. 36,
1295–1299.
Klaenhammer, T.R., 1988. Bacteriocins of lactic acid bacteria. Biochimie 70,
337–349.
Kluskens, L.D., Kuipers, A., Rink, R., de Boef, E., Fekken, S., Driessen, A.J., Kuipers,
O.P., Moll, G.N., 2005. Post-translational modification of therapeutic peptides by
NisB, the dehydratase of the lantibiotic nisin. Biochemistry 44, 12827–12834.
Knerr, P.J., van der Donk, W.A., 2012. Discovery, biosynthesis, and engineering of
lantipeptides. Annu. Rev. Biochem. 81, 479–505.
Kodani, S., Hudson, M.E., Durrant, M.C., Buttner, M.J., Nodwell, J.R., Willey, J.M., 2004.
The SapB morphogen is a lantibiotic-like peptide derived from the product of the
developmental gene ramS in Streptomyces coelicolor. PNAS 101, 11448–11453.
Kodani, S., Lodato, M.A., Durrant, M.C., Picart, F., Willey, J.M., 2005. SapTa
lanthionine-containing peptide involved in aerial hyphae formation in the strep-
tomycetes. Mol. Microbiol. 58, 1368–1380.
Kordel, M., Benz, R., Sahl, H.G., 1988. Mode of action of the staphylococcin like
peptide Pep 5: voltage-dependent depolarization of bacterial and artificial mem-
branes. J. Bacteriol. 170, 84–88.
Krawczyk, B., Voller, G.H., Voller, J., Ensle, P., Suessmuth, R.D., 2012. Curvopeptin: a
new lanthionine-containing class III lantibiotic and its co-substrate promiscuous
synthetase. ChemBioChem 13, 2065–2071.
Kruszewska, D., Sahl, H.-G., Bierbaum, G., Pag, U., Hynes, S.O., Ljungh, A., 2004.
Mersacidin eradicates methicillin-resistant Staphylococcus aureus (MRSA) in a
mouse rhinitis model. J. Antimicrob. Chemother. 54, 648–653.
Kuipers, O.P., Beerthuyzen, M.M., Ruyter, P.G., de Luesink, E.J., de Vos, W.M., 1995.
Autoregulation of nisin biosynthesis in Lactococcus lactis by signal transduction.
J. Biol. Chem. 270, 27299–27304.
Levengood, M.R., Patton, G.C., van der Donk, W.A., 2007. The leader peptide is not
required for posttranslational modification by lacticin 481 synthetase. J. Am.
Chem. Soc. 129, 10314–10315.
Li, B., Sher, D., Kelly, L., Shi, Y., Huang, K., Knerr, P.J., Joewono, I., Rusch, D., Chisholm,
S.W., van der Donk, W.A., 2010. Catalytic promiscuity in the biosynthesis of cyclic
peptide secondary metabolites in planktonic marine cyanobacteria. PNAS 107,
10430–10435.
Li, P., Li, X., Saravanan, R., Li, C.M., Leong, S.S.J., 2012. Antimicrobial macromolecules:
synthesis methods and future applications. RSC Adv. 2, 4031–4044.
Lohans, C.T., Huang, Z., van Belkum, M.J., Giroud, M., Sit, C.S., Steels, E.M., Zheng, J.,
Whittal, R.M., McMullen, L.M., Vederas, J.C., 2012. Structural characterization
of the highly cyclized lantibiotic Paenicidin A via a partial desulfuriza-
tion/reduction strategy. J. Am. Chem. Soc. 134, 19540–19543.
Makino, A., Baba, T., Fujimoto, K., Iwamoto, K., Yano, Y., Terada, N., Ohno, S., Sato, S.B.,
Ohta, A., Umeda, M., Matsuzaki, K., Kobayashi, T., 2003. Cinnamycin (Ro 09-0198)
promotes cell binding and toxicity by inducing transbilayer lipid movement. J.
Biol. Chem. 278, 3204–3209.
Märki, F., Hänni, E., Fredenhagen, A., van Oostrum, J., 1991. Mode of action of the
lanthionine-containing peptide antibiotics duramycin, duramycin B and C, and
cinnamycin as indirect inhibitors of phospholipase A2. Biochem. Pharmacol. 42,
2027–2035.
Mantovani, H.C., Hu, H., Worobo, R.W., Russell, J.B., 2002. Bovicin HC5, a bacteriocin
from Streptococcus bovis HC5. Microbiology 148, 3347–3352.
Mantovani, H.C., Russell, J.B., 2008. Bovicin HC5 a lantibiotic produced by Strepto-
coccus bovis HC5, catalyzes the efflux of intracellular potassium but not ATP.
Antimicrob. Agents Chemother. 52, 2247–2249.
Marsh, A., O’Sullivan, O., Ross, R.P., Cotter, P., Hill, C., 2010. In silico analysis high-
lights the frequency and diversity of type 1 lantibiotic gene clusters in genome
sequenced bacteria. BMC Genom. 11, 679.
Meindl, K., Schmiederer, T., Schneider, K., Reicke, A., Butz, D., Keller, S., Gühring, H.,
Vértesy, L., Wink, J., Hoffmann, H., Brönstrup, M., Sheldrick, G.M., Süssmuth, R.D.,
2010. Labyrinthopeptins: a new class of carbacyclic lantibiotics. Angew. Chem.
49, 1151–1154.
Morgan, S.M., O’Connor, P.M., Cotter, P.D., Ross, R.P., Hill, C., 2005. Sequential actions
of the two component peptides of the lantibiotic lacticin 3147 explain its antimi-
crobial activity at nanomolar concentrations. Antimicrob. Agents Chemother. 49,
2606–2611.
Müller, W.M., Ensle, P., Krawczyk, B., Suessmuth, R.D., 2011. Leader peptide-directed
processing of labyrinthopeptin A2 precursor peptide by the modifying enzyme
LabKC. Biochemistry 50, 8362–8373.
Müller, W.M., Schmiederer, T., Ensle, P., Suessmuth, R.D., 2010. In vitro biosyn-
thesis of the prepeptide of type-III lantibiotic labyrinthopeptin A2 including
formation of a C C bond as a post-translational modification. Angew. Chem.
49, 2436–2440.
Nagao, J., Morinaga, Y., Islam, M.R., Asaduzzaman, S.M., Aso, Y., Nakayama, J.,
Sonomoto, K., 2009. Mapping and identification of the region and secondary
structure required for the maturation of the nukacin ISK-1 prepeptide. Peptides
30, 1412–1420.
Naruse, N., Tenmyo, O., Tomita, K., Konishi, M., Miyaki, T., Kawaguchi, H., Shiba, T.,
1989. Lanthiopeptin, a new peptide antibiotic. Production, isolation and prop-
erties of lanthiopeptin. J. Antibiot. 42, 837–845.
Oliynyk, I., Varelogianni, G., Roomans, G.M., Johannesson, M., 2010. Effect of
duramycin on chloride transport and intracellular calcium concentration in cys-
tic fibrosis and non-cystic fibrosis epithelia. A.P.M.I.S 118, 982–990.
61
Ösapay, G., Prokai, L., Kim, H.S., Medzihradszky, K.F., Coy, D.H., Liapakis, G., Rei-
sine, T., Melacini, G., Zhu, Q., Wang, S.H., Mattern, R.H., Goodman, M., 1997.
Lanthionine-somatostatin analogs: synthesis, characterization, biological activ-
ity, and enzymatic stability studies. J. Med. Chem. 40, 2241–2251.
Paul, M., Patton, G.C., van der Donk, W.A., 2007. Mutants of the zinc ligands of lac-
ticin 481 synthetase retain dehydration activity but have impaired cyclization
activity. Biochemistry 46, 6268–6276.
Rew, Y., Malkmus, S., Svensson, C., Yaksh, T.L., Chung, N.N., Schiller, P.W., Cassel, J.A.,
DeHaven, R.N., Taulane, J.P., Goodman, M., 2002. Synthesis and biological activ-
ities of cyclic lanthionine enkephalin analogues: delta-opioid receptor selective
ligands. J. Med. Chem. 45, 3746–3754.
Rink, R., Kuipers, A., de Boef, E., Leenhouts, K.J., Driessen, A.J., Moll, G.N., Kuipers, O.P.,
2005. Lantibiotic structures as guidelines for the design of peptides that can be
modified by lantibiotic enzymes. Biochemistry 44, 8873–8882.
Roberts, M., Hladky, S.B., Pickles, R.J., Cuthbert, A.W., 1991. Stimulation of sodium
transport by duramycin in cultured human colonic epithelia. J. Pharmacol. Exp.
Ther. 259, 1050–1058.
Rodríguez-Valera, F., Juez, J., Kushner, D.J., 1982. Halocins: salt dependent bacteri-
ocins produced by extremely halophilic rods. Can. J. Microbiol. 28, 151–154.
Rogers, L.A., 1928. The inhibiting effect of Streptococcus lactis on Lactobacillus bul-
garicus. J. Bacteriol. 16, 321–325.
Ross, A.C., Vederas, J.C., 2010. Fundamental functionality: recent developments
in understanding the structure-activity relationships of lantibiotic peptides. J.
Antibiot. (Tokyo) 64, 27–34.
Sahl, H.G., Bierbaum, G., 1998. Lantibiotics: biosynthesis and biological activities of
uniquely modified peptides from Gram-positive bacteria. Annu. Rev. Microbiol.
52, 41–79.
Sahl, H.G., Brandis, H., 1982. Mode of action of the staphylococcin-like peptide Pep 5
and culture conditions affecting its activity. Zentralbl. Bakteriol. Mikrobiol. Hyg.
252, 166–175.
Sandiford, S., Kay, P., Upton, M., 2010. The use of antimicrobial peptides in the pre-
vention of biofilm forming S. epidermidis strains associated with orthopaedic
infection. In: Seventh SICOT/SIROT Annual International Conference and SOF
Ortopediveckan, Gothenburg.
Sawa, N., Wilaipun, P., Kinoshita, S., Zendo, T., Leelawatcharamas, V., Nakayama, J.,
Sonomoto, K., 2012. Isolation and characterization of enterocin W a novel two-
peptide lantibiotic produced by Enterococcus faecalis NKR-4-1. Appl. Environ.
Microbiol. 78, 900–903.
Schmitz, S., Hoffmann, A., Szekat, C., Rudd, B., Bierbaum, G., 2006. The lantibiotic
mersacidin is an autoinducing peptide. Appl. Environ. Microbiol. 72, 7270–7277.
Schnell, N., Entian, K.D., Schneider, U., Götz, F., Zähner, H., Kellner, R., Jung, G., 1988.
Prepeptide sequence of epidermin, a ribosomally synthesized antibiotic with
four sulphide-rings. Nature 333, 276–278.
Siezen, R.J., Kuipers, O.P., de Vos, W.M., 1996. Comparison of lantibiotic gene clusters
and encoded proteins. Antonie Van Leeuwenhoek 69, 171–184.
Simone, M., Monciardini, P., Gaspari, E., Donadio, S., Maffioli, S.I., 2013. Isolation
and characterization of NAI-802, a new lantibiotic produced by two different
Actinoplanes strains. J. Antibiot. (Tokyo) 66, 73–78.
Stevens, K.A., Sheldon, B.W., Klapes, N.A., Klaenhammer, T.R., 1991. Nisin treatment
for inactivation of Salmonella species and other Gram-negative bacteria. Appl.
Environ. Microbiol. 57, 3613–3615.
Suda, S., Cotter, P.D., Hill, C., Ross, R.P., 2011. Lacticin 3147 – biosynthesis, molecular
analysis, immunity, bioengineering and applications. Curr. Protein Pept. Sci. 13,
193–204.
Szekat, C., Jack, R.W., Skutlarek, D., Färber, H., Bierbaum, G., 2003. Construction of an
expression system for site-directed mutagenesis of the lantibiotic mersacidin.
Appl. Environ. Microbiol. 69, 3777–3783.
Tagg, J.R., Dajani, A.S., Wannamaker, L.W., 1976. Bacteriocins of Gram-positive bacte-
ria. Bacteriol. Rev. 40, 722–756.
Tang, W., van der Donk, W.A., 2012. Structural characterization of four prochlorosins:
a novel class of lantipeptides produced by planktonic marine cyanobacteria.
Biochemistry 51, 4271–4279.
Tang, W., van der Donk, W.A., 2013. The sequence of the enterococcal
cytolysin imparts unusual lanthionine stereochemistry. Nat. Chem. Biol.,
http://dx.doi.org/10.1038/nchembio.1162 (2013 Jan 13 [Epub ahead of print]
PubMed PMID: 23314913).
Teng, Y., Zhao, W., Qian, C., Li, O., Zhu, L., Wu, X., 2012. Gene cluster analysis for the
biosynthesis of elgicins, novel lantibiotics produced by Paenibacillus elgii B69.
BMC Microbiol. 12, 45.
van Heel, A.J., Montalban-Lopez, M., Kuipers, O.P., 2011. Evaluating the feasibility
of lantibiotics as an alternative therapy against bacterial infections in humans.
Expert Opin. Drug Metab. Toxicol. 7, 675–680.
van Kraaij, C., de Vos, W.M., Siezen, R., Kuipers, O.P., 1999. Lantibiotics: biosynthesis
mode of action and applications. Nat. Prod. Rep. 16, 575–587.
Voeller, G.H., Krawczyk, J.M., Pesic, A., Krawczyk, B., Nachtigall, J., Süssmuth,
R.D., 2012. Characterization of new Class III Lantibiotics—Erythreapeptin,
Avermipeptin and Griseopeptin from Saccharopolyspora erythraea, Streptomyces
avermitilis and Streptomyces griseus demonstrates stepwise N-Terminal leader
processing. ChemBioChem 13 (8), 1174–1183.
Wang, H., van der Donk, W.A., 2012. Biosynthesis of the class III lantipeptide
catenulipeptin. ACS Chem. Biol. 7, 1529–1535.
Wescombe, P.A., Dyet, K.H., Dierksen, K.P., Power, D.A., Jack, R.W., Burton, J.P.,
Inglis, M.A., Wescombe, A.L., Tagg, J.R., 2012. Salivaricin G32, a homolog
of the prototype Streptococcus pyogenes nisin-like lantibiotic SA-FF22, pro-
duced by the commensal species Streptococcus salivarius. Int. J. Microbiol.,
http://dx.doi.org/10.1155/2012/738503 (in press).
62 J. Dischinger et al. / International Journal of Medical Microbiology 304 (2014) 51–62
Wiedemann, I., Benz, R., Sahl, H.G., 2004. Lipid II-mediated pore formation by
the peptide antibiotic nisin: a black lipid membrane study. J. Bacteriol. 186,
3259–3261.
Wiedemann, I., Böttiger, T., Bonelli, R.R., Wiese, A., Hagge, S.O., Gutsmann, T., Sey-
del, U., Deegan, L., Hill, C., Ross, P., Sahl, H.G., 2006. The mode of action of the
lantibiotic lacticin 3147 – a complex mechanism involving specific interaction
of two peptides and the cell wall precursor lipid II. Mol. Microbiol. 61, 285–296.
Wiedemann, I., Breukink, E., van Kraaij, C., Kuipers, O.P., Bierbaum, G., Kruijff, B., de
Sahl, H.G., 2001. Specific binding of nisin to the peptidoglycan precursor lipid
II combines pore formation and inhibition of cell wall biosynthesis for potent
antibiotic activity. J. Biol. Chem. 276, 1772–1779.
Willey, J.M., van der Donk, W.A., 2007. Lantibiotics: peptides of diverse structure
and function. Ann. Rev. Microbiol. 61, 477–501.
Willey, J.M., Willems, A., Kodani, S., Nodwell, J.R., 2006. Morphogenetic surfactants
and their role in the formation of aerial hyphae in Streptomyces coelicolor. Mol.
Microbiol. 59, 731–742.
Wilson-Stanford, S., Smith, L., 2011. Commercial development and appli-
cation of type A lantibiotics. Recent Pat. Antiinfect. Drug Discov. 6,
175–185.
Yonezawa, H., Kuramitsu, H.K., 2005. Genetic analysis of a unique bacteriocin,
Smb, produced by Streptococcus mutans GS5. Antimicrob. Agents Chemother.
49, 541–548.
Zaehner, H., Goetz, F., Hoerner, T., Werner, R.G., Allgaier, H., Jung, G., Kellner, R.,
1998. New peptide antibiotic gallidermin is produced by Staphylococcus gal-
linarum and used esp. for treating eczema, impetigo, cellulitis and acne. U.S.
patent 5,843,709-A.