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Lantibiotics

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Gallidermin
Identifiers
SymbolGallidermin
PfamPF02052
InterProIPR006079
SCOP21mqy / SCOPe / SUPFAM
TCDB1.C.20
OPM superfamily161
OPM protein1mqy
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

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".[1] 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

Some contain 2 peptides, e.g. haloduracin.[6]

Examples

Lantibiotic Type # of
residues		 # of
thioether links		 Other
links[clarification needed]		 refs
nisin
subtilin		 A 34 5 0
gallidermin
epidermin		 A 21 3 1 [2]
mersacidin B 20 4 [3]
actagardine B 19 4 0
cinnamycin
duramycin		 B 19 3 1 [5]
sublancin 168 ? 37 1 2 [7]
plantaricin C B 27 4 0

(Sublancin may be an S-linked glycopeptide).[8]

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.[9] There are four known enzymes (lanthipeptide synthetases) responsible for producing lanthionine rings.[10][11]

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.[12] They are active in very low concentrations.[13]

Application

Food preservation

Lantibiotics are produced by Gram-positive bacteria and show strong antimicrobial action toward a wide range of other Gram-positive bacteria.[14] 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).[14]

Clinical antibiotic

One type known as B lantibiotic NVB302 entered phase 1 clinical trials in 2011 for use against Clostridium difficile,[15] and reported good results in 2012.[16]

Databases

BACTIBASE is an open-access database for bacteriocins including lantibiotics.[17][18] LANTIBASE is a lantibiotic specific resource.[19]

References

  1. ^ Chatterjee C, Paul M, Xie L, van der Donk WA (February 2005). "Biosynthesis and mode of action of lantibiotics". Chem. Rev. 105 (2): 633–84. doi:10.1021/cr030105v. PMID 15700960.
  2. ^ a b Kellner R, Jung G, Hörner T, Zähner H, Schnell N, Entian KD, Götz F (October 1988). "Gallidermin: a new lanthionine-containing polypeptide antibiotic". Eur. J. Biochem. 177 (1): 53–9. doi:10.1111/j.1432-1033.1988.tb14344.x. PMID 3181159.
  3. ^ a b Sass P, Jansen A, Szekat C, Sass V, Sahl HG, Bierbaum G (2008). "The lantibiotic mersacidin is a strong inducer of the cell wall stress response of Staphylococcus aureus". BMC Microbiol. 8: 186. doi:10.1186/1471-2180-8-186. PMC 2592248. PMID 18947397.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  4. ^ Brötz H, Bierbaum G, Markus A, Molitor E, Sahl HG (March 1995). "Mode of action of the lantibiotic mersacidin: inhibition of peptidoglycan biosynthesis via a novel mechanism?". Antimicrob. Agents Chemother. 39 (3): 714–9. doi:10.1128/AAC.39.3.714. PMC 162610. PMID 7793878.
  5. ^ a b Makino A, Baba T, Fujimoto K, Iwamoto K, Yano Y, Terada N, Ohno S, Sato SB, Ohta A, Umeda M, Matsuzaki K, Kobayashi T (January 2003). "Cinnamycin (Ro 09-0198) promotes cell binding and toxicity by inducing transbilayer lipid movement". J. Biol. Chem. 278 (5): 3204–9. doi:10.1074/jbc.M210347200. PMID 12446685.
  6. ^ Cooper LE, McClerren AL, Chary A, van der Donk WA (October 2008). "Structure-activity relationship studies of the two-component lantibiotic haloduracin". Chem. Biol. 15 (10): 1035–45. doi:10.1016/j.chembiol.2008.07.020. PMC 2633096. PMID 18940665.
  7. ^ Stein T (May 2005). "Bacillus subtilis antibiotics: structures, syntheses and specific functions". Mol. Microbiol. 56 (4): 845–57. doi:10.1111/j.1365-2958.2005.04587.x. PMID 15853875. S2CID 20144405.
  8. ^ Oman TJ, Boettcher JM, Wang H, Okalibe XN, van der Donk WA (February 2011). "Sublancin is not a lantibiotic but an S-linked glycopeptide". Nat. Chem. Biol. 7 (2): 78–80. doi:10.1038/nchembio.509. PMC 3060661. PMID 21196935.
  9. ^ Siegers K, Heinzmann S, Entian KD (May 1996). "Biosynthesis of lantibiotic nisin. Posttranslational modification of its prepeptide occurs at a multimeric membrane-associated lanthionine synthetase complex". J. Biol. Chem. 271 (21): 12294–301. doi:10.1074/jbc.271.21.12294. PMID 8647829.
  10. ^ Goto, Y; Li, B; Claesen, J; Shi, Y; Bibb, MJ; van der Donk, WA (2010). "Discovery of unique lanthionine synthetases reveals new mechanistic and evolutionary insights". PLOS Biology. 8 (3): e1000339. doi:10.1371/journal.pbio.1000339. PMC 2843593. PMID 20351769.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  11. ^ Zhang, Q; Yu, Y; Vélasquez, JE; van der Donk, WA (2012). "Evolution of lanthipeptide synthetases". Proceedings of the National Academy of Sciences. 109 (45): 18361–6. Bibcode:2012PNAS..10918361Z. doi:10.1073/pnas.1210393109. PMC 3494888. PMID 23071302.
  12. ^ Brötz H, Sahl HG (2000). "New insights into the mechanism of action of lantibiotics—diverse biological effects by binding to the same molecular target". Journal of Antimicrobial Chemotherapy. 46 (1): 1–6. doi:10.1093/jac/46.1.1. PMID 10882681.
  13. ^ Cotter, Hill, Ross (2005). "Bacterial Lantibiotics: Strategies to Improve Therapeutic Potential" (PDF). Current Protein & Peptide Science. 6 (1): 61–75. doi:10.2174/1389203053027584. PMID 15638769. Archived from the original (PDF) on 2007-09-28. Retrieved 2007-06-01.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  14. ^ a b van Kraaij C, de Vos WM, Siezen RJ, Kuipers OP (October 1999). "Lantibiotics: biosynthesis, mode of action and applications". Nat Prod Rep. 16 (5): 575–87. CiteSeerX 10.1.1.546.6212. doi:10.1039/a804531c. PMID 10584332.
  15. ^ "New antibiotic compound enters phase I clinical trial". Press Release. Wellcome Trust. 2011-11-03.
  16. ^ Parker S (2012-08-06). "Novacta Biosystems Limited completes Phase I study of NVB302 against C. difficile infection in healthy volunteers". Press Release. Celtic Pharma Holding. Archived from the original on 2013-09-01. Retrieved 2013-03-23.
  17. ^ Hammami R, Zouhir A, Ben Hamida J, Fliss I (2007). "BACTIBASE: a new web-accessible database for bacteriocin characterization". BMC Microbiology. 7: 89. doi:10.1186/1471-2180-7-89. PMC 2211298. PMID 17941971.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  18. ^ Hammami R, Zouhir A, Le Lay C, Ben Hamida J, Fliss I (2010). "BACTIBASE second release: a database and tool platform for bacteriocin characterization". BMC Microbiology. 10: 22. doi:10.1186/1471-2180-10-22. PMC 2824694. PMID 20105292.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  19. ^ "DBT Centre for Bioinformatics Presidency University, Kolkata". Archived from the original on 2013-08-15. Retrieved 2013-07-25.

Further reading

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