lantibiotics

{{Infobox protein family

| Symbol = Gallidermin

| Name = Gallidermin

| image =

| width =

| caption =

| Pfam= PF02052

| InterPro= IPR006079

| SMART=

| Prosite =

| SCOP = 1mqy

| TCDB = 1.C.20

| OPM family= 161

| OPM protein= 1mqy

| PDB=

}}

Lantibiotics are a class of polycyclic peptide antibiotics that contain the characteristic thioether amino acids lanthionine or methyllanthionine, as well as the unsaturated amino acids dehydroalanine, and 2-aminoisobutyric acid. They belong to ribosomally synthesized and post-translationally modified peptides.

Lanthionine is composed of two alanine residues that are crosslinked on their β-carbon atoms by a thioether (monosulfide) linkage.

Lantibiotics are produced by a large number of Gram-positive bacteria such as Streptococcus and Streptomyces to attack other Gram-positive bacteria, and as such, they are considered a member of the bacteriocins. Bacteriocins are classified according to their extent of posttranslational modification. The lantibiotics are a class of more extensively modified bacteriocins, also called Class I bacteriocins. (Bacteriocins for which disulfide bonds are the only modification to the peptide are Class II bacteriocins.)

Lantibiotics are well studied because of the commercial use of these bacteria in the food industry for making dairy products such as cheese.

Nisin and epidermin are members of a family of lantibiotics that bind to lipid II, a cell wall precursor lipid component of target bacteria and disrupt cell wall production. The duramycin family of lantibiotics binds phosphoethanolamine in the membranes of its target cells and seem to disrupt several physiological functions.

History

The name lantibiotics was introduced in 1988 as an abbreviation for "lanthionine-containing peptide antibiotics".{{cite journal |vauthors=Chatterjee C, Paul M, Xie L, van der Donk WA | title = Biosynthesis and mode of action of lantibiotics | journal = Chem. Rev. | volume = 105 | issue = 2 | pages = 633–84 |date=February 2005 | pmid = 15700960 | doi = 10.1021/cr030105v }} The first structures of these antimicrobial agents were produced by pioneering work by Gross and Morell in the late 1960s and early 1970s, thus marking the formal introduction of lantibiotics. Since then, lantibiotics such as nisin have been used auspiciously for food preservation and have yet to encounter significant bacterial resistance. These attributes of lantibiotics have led to more detailed research into their structures and biosynthetic pathways.

Classification

Type A lantibiotics are long flexible molecules - e.g., nisin, bisin, subtilin, epidermin, gallidermin{{cite journal |vauthors=Kellner R, Jung G, Hörner T, Zähner H, Schnell N, Entian KD, Götz F | title = Gallidermin: a new lanthionine-containing polypeptide antibiotic | journal = Eur. J. Biochem. | volume = 177 | issue = 1 | pages = 53–9 |date=October 1988 | pmid = 3181159 | doi =10.1111/j.1432-1033.1988.tb14344.x }} Subgroup AI includes mutacin II; subgroup AII includes mutacin I and III.
Type B lantibiotics are globular - e.g., mersacidin.{{cite journal |vauthors=Sass P, Jansen A, Szekat C, Sass V, Sahl HG, Bierbaum G | title = The lantibiotic mersacidin is a strong inducer of the cell wall stress response of Staphylococcus aureus | journal = BMC Microbiol. | volume = 8| pages = 186 | year = 2008 | pmid = 18947397 | pmc = 2592248 | doi = 10.1186/1471-2180-8-186 | doi-access = free }}{{cite journal |vauthors=Brötz H, Bierbaum G, Markus A, Molitor E, Sahl HG | title = Mode of action of the lantibiotic mersacidin: inhibition of peptidoglycan biosynthesis via a novel mechanism? | journal = Antimicrob. Agents Chemother. | volume = 39 | issue = 3 | pages = 714–9 |date=March 1995 | pmid = 7793878 | pmc = 162610 | doi =10.1128/AAC.39.3.714 }} actagardine, duramycin, and cinnamycin.{{cite journal |vauthors=Makino A, Baba T, Fujimoto K, Iwamoto K, Yano Y, Terada N, Ohno S, Sato SB, Ohta A, Umeda M, Matsuzaki K, Kobayashi T | title = Cinnamycin (Ro 09-0198) promotes cell binding and toxicity by inducing transbilayer lipid movement | journal = J. Biol. Chem. | volume = 278 | issue = 5 | pages = 3204–9 |date=January 2003 | pmid = 12446685 | doi = 10.1074/jbc.M210347200 | doi-access = free }}

Some contain 2 peptides, e.g. haloduracin.{{cite journal |vauthors=Cooper LE, McClerren AL, Chary A, van der Donk WA | title = Structure-activity relationship studies of the two-component lantibiotic haloduracin | journal = Chem. Biol. | volume = 15 | issue = 10 | pages = 1035–45 |date=October 2008 | pmid = 18940665 | pmc = 2633096 | doi = 10.1016/j.chembiol.2008.07.020 }}

= Examples =

Lantibiotic	Type	# of residues	# of thioether links	Other links{{clarify\|date=December 2016}}	refs
class="wikitable"
nisin subtilin	A	34	5	0
gallidermin epidermin	A	21	3	1
mersacidin	B	20	4
actagardine	B	19	4	0
cinnamycin duramycin	B	19	3	1
sublancin 168	?	37	1	2	{{cite journal \| author = Stein T \| title = Bacillus subtilis antibiotics: structures, syntheses and specific functions \| journal = Mol. Microbiol. \| volume = 56 \| issue = 4 \| pages = 845–57 \|date=May 2005 \| pmid = 15853875 \| doi = 10.1111/j.1365-2958.2005.04587.x \| s2cid = 20144405 \| doi-access = free }}
plantaricin C	B	27	4	0

(Sublancin may be an S-linked glycopeptide).{{cite journal |vauthors=Oman TJ, Boettcher JM, Wang H, Okalibe XN, van der Donk WA | title = Sublancin is not a lantibiotic but an S-linked glycopeptide | journal = Nat. Chem. Biol. | volume = 7 | issue = 2 | pages = 78–80 |date=February 2011 | pmid = 21196935 | pmc = 3060661 | doi = 10.1038/nchembio.509 }}

Biosynthesis

They are synthesised with a leader polypeptide sequence that is removed only during the transport of the molecule out of the synthesising cell. They are synthesized by ribosomes, which distinguishes them from most natural antibiotics.{{cite journal |vauthors=Siegers K, Heinzmann S, Entian KD | title = Biosynthesis of lantibiotic nisin. Posttranslational modification of its prepeptide occurs at a multimeric membrane-associated lanthionine synthetase complex | journal = J. Biol. Chem. | volume = 271 | issue = 21 | pages = 12294–301 |date=May 1996 | pmid = 8647829 | doi = 10.1074/jbc.271.21.12294| doi-access = free }} There are four known enzymes (lanthipeptide synthetases) responsible for producing lanthionine rings.{{Cite journal | pmid = 20351769 | year = 2010 | last1 = Goto | first1 = Y | last2 = Li | first2 = B | last3 = Claesen | first3 = J | last4 = Shi | first4 = Y | last5 = Bibb | first5 = MJ | last6 = van der Donk | first6 = WA | title = Discovery of unique lanthionine synthetases reveals new mechanistic and evolutionary insights | volume = 8 | issue = 3 | pages = e1000339 | doi = 10.1371/journal.pbio.1000339 | pmc = 2843593 | journal = PLOS Biology | doi-access = free }}{{Cite journal | pmid = 23071302 | year = 2012 | last1 = Zhang | first1 = Q | last2 = Yu | first2 = Y | last3 = Vélasquez | first3 = JE | last4 = van der Donk | first4 = WA | title = Evolution of lanthipeptide synthetases| volume = 109 | issue = 45 | pages = 18361–6 | doi = 10.1073/pnas.1210393109 | pmc = 3494888 | journal = Proceedings of the National Academy of Sciences| bibcode = 2012PNAS..10918361Z | doi-access = free }}

Mechanism of action

Lantibiotics show substantial specificity for some components (e.g., lipid II) of bacterial cell membranes especially of Gram-positive bacteria. Type A lantibiotics kill rapidly by pore formation, type B lantibiotics inhibit peptidoglycan biosynthesis.{{cite journal |vauthors=Brötz H, Sahl HG|year=2000 |title=New insights into the mechanism of action of lantibiotics—diverse biological effects by binding to the same molecular target |journal=Journal of Antimicrobial Chemotherapy |pmid=10882681 |doi=10.1093/jac/46.1.1 |volume=46 |issue=1 |pages=1–6|doi-access=free }} They are active in very low concentrations.{{cite journal |url=http://www.bentham.org/cpps/sample/cpps6-1/0007K.pdf |title=Bacterial Lantibiotics: Strategies to Improve Therapeutic Potential |author=Cotter, Hill, Ross |journal=Current Protein & Peptide Science |year=2005 |volume=6 |issue=1 |pages=61–75 |doi=10.2174/1389203053027584 |pmid=15638769 |access-date=2007-06-01 |archive-url=https://web.archive.org/web/20070928025815/http://www.bentham.org/cpps/sample/cpps6-1/0007K.pdf |archive-date=2007-09-28 |url-status=dead }}

Application

= Food preservation =

Lantibiotics are produced by Gram-positive bacteria and show strong antimicrobial action toward a wide range of other Gram-positive bacteria. As such, they have become attractive candidates for use in food preservation (by inhibiting pathogens that cause food spoilage) and the pharmaceutical industry (to prevent or fight infections in humans or animals).{{cite journal |vauthors=van Kraaij C, de Vos WM, Siezen RJ, Kuipers OP | title = Lantibiotics: biosynthesis, mode of action and applications | journal = Nat Prod Rep | volume = 16 | issue = 5 | pages = 575–87 |date=October 1999 | pmid = 10584332 | doi =10.1039/a804531c | citeseerx =10.1.1.546.6212 }}

= Clinical antibiotic =

One type known as B lantibiotic NVB302 entered phase 1 clinical trials in 2011 for use against Clostridioides difficile,{{cite web | url = http://www.wellcome.ac.uk/News/2011/News/WTVM053339.htm | title = New antibiotic compound enters phase I clinical trial | date = 2011-11-03 | work = Press Release | publisher = Wellcome Trust }} and reported good results in 2012.{{cite web | url = http://www.celticpharmaholdings.com/component/k2/item/5-novacta-biosystems-limited-completes-phase-i-study-of-nvb302-against-c-difficile-infection-in-healthy-volunteers | title = Novacta Biosystems Limited completes Phase I study of NVB302 against C. difficile infection in healthy volunteers | author = Parker S | date = 2012-08-06 | work = Press Release | publisher = Celtic Pharma Holding | access-date = 2013-03-23 | archive-url = https://web.archive.org/web/20130901115657/http://celticpharmaholdings.com/component/k2/item/5-novacta-biosystems-limited-completes-phase-i-study-of-nvb302-against-c-difficile-infection-in-healthy-volunteers | archive-date = 2013-09-01 | url-status = dead }}

Databases

BACTIBASE is an open-access database for bacteriocins including lantibiotics.{{cite journal |title=BACTIBASE: a new web-accessible database for bacteriocin characterization |vauthors=Hammami R, Zouhir A, Ben Hamida J, Fliss I |journal=BMC Microbiology |year=2007 |volume=7 |pages=89 |pmid=17941971 |doi=10.1186/1471-2180-7-89 |pmc=2211298 |doi-access=free }}{{cite journal |title=BACTIBASE second release: a database and tool platform for bacteriocin characterization |vauthors=Hammami R, Zouhir A, Le Lay C, Ben Hamida J, Fliss I |journal=BMC Microbiology |year=2010 |volume=10 |pages=22 |pmid=20105292 |doi=10.1186/1471-2180-10-22 |pmc=2824694 |doi-access=free }} LANTIBASE is a lantibiotic specific resource.{{cite web |url=http://bioinfo-presiuniv.edu.in/lantibase_about.php |title=DBT Centre for Bioinformatics Presidency University, Kolkata |access-date=2013-07-25 |url-status=dead |archive-url=https://web.archive.org/web/20130815113818/http://bioinfo-presiuniv.edu.in/lantibase_about.php |archive-date=2013-08-15 }}

References

External links

[https://lantibase.weebly.com/ Lantibase], a database of lantibiotics
{{cite web | url = http://bactibase.hammamilab.org/bacteriocinslist.php?Class=lantibiotic | title = Complete list of lantibiotics | work = BACTIBASE Database}}

Category:Peripheral membrane proteins