Lantibiotics

Last updated
Gallidermin
Identifiers
SymbolGallidermin
Pfam PF02052
InterPro IPR006079
SCOP2 1mqy / SCOPe / SUPFAM
TCDB 1.C.20
OPM superfamily 161
OPM protein 1mqy
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure 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.

Contents

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

LantibioticType# of
residues		# of
thioether links		Other
links[ clarification needed ]		refs
nisin
subtilin		A3450
gallidermin
epidermin		A2131 [2]
mersacidinB204 [3]
actagardineB1940
cinnamycin
duramycin		B1931 [5]
sublancin 168 ?3712 [7]
plantaricin C B2740

(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 Clostridioides 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]

Related Research Articles

<span class="mw-page-title-main">Gram-negative bacteria</span> Group of bacteria that do not retain the Gram stain used in bacterial differentiation

Gram-negative bacteria are bacteria that, unlike gram-positive bacteria, do not retain the crystal violet stain used in the Gram staining method of bacterial differentiation. Their defining characteristic is their cell envelope, which consists of a thin peptidoglycan cell wall sandwiched between an inner (cytoplasmic) membrane and an outer membrane. These bacteria are found in all environments that support life on Earth.

Peptidoglycan or murein is a unique large macromolecule, a polysaccharide, consisting of sugars and amino acids that forms a mesh-like layer (sacculus) that surrounds the bacterial cytoplasmic membrane. The sugar component consists of alternating residues of β-(1,4) linked N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM). Attached to the N-acetylmuramic acid is an oligopeptide chain made of three to five amino acids. The peptide chain can be cross-linked to the peptide chain of another strand forming the 3D mesh-like layer. Peptidoglycan serves a structural role in the bacterial cell wall, giving structural strength, as well as counteracting the osmotic pressure of the cytoplasm. This repetitive linking results in a dense peptidoglycan layer which is critical for maintaining cell form and withstanding high osmotic pressures, and it is regularly replaced by peptidoglycan production. Peptidoglycan hydrolysis and synthesis are two processes that must occur in order for cells to grow and multiply, a technique carried out in three stages: clipping of current material, insertion of new material, and re-crosslinking of existing material to new material.

<span class="mw-page-title-main">Bacteriocin</span> Class of bacterially produced peptide antibiotics

Bacteriocins are proteinaceous or peptidic toxins produced by bacteria to inhibit the growth of similar or closely related bacterial strain(s). They are similar to yeast and paramecium killing factors, and are structurally, functionally, and ecologically diverse. Applications of bacteriocins are being tested to assess their application as narrow-spectrum antibiotics.

<span class="mw-page-title-main">Lanthionine</span> Chemical compound

Lanthionine is a nonproteinogenic amino acid with the chemical formula (HOOC-CH(NH2)-CH2-S-CH2-CH(NH2)-COOH). It is typically formed by a cysteine residue and a dehydrated serine residue. Despite its name, lanthionine does not contain the element lanthanum.

<span class="mw-page-title-main">Nisin</span> Chemical compound

Nisin is a polycyclic antibacterial peptide produced by the bacterium Lactococcus lactis that is used as a food preservative. It has 34 amino acid residues, including the uncommon amino acids lanthionine (Lan), methyllanthionine (MeLan), didehydroalanine (Dha), and didehydroaminobutyric acid (Dhb). These unusual amino acids are introduced by posttranslational modification of the precursor peptide. In these reactions a ribosomally synthesized 57-mer is converted to the final peptide. The unsaturated amino acids originate from serine and threonine, and the enzyme-catalysed addition of cysteine residues to the didehydro amino acids result in the multiple (5) thioether bridges.

<span class="mw-page-title-main">Polymyxin</span> Group of antibiotics

Polymyxins are antibiotics. Polymyxins B and E are used in the treatment of Gram-negative bacterial infections. They work mostly by breaking up the bacterial cell membrane. They are part of a broader class of molecules called nonribosomal peptides.

<span class="mw-page-title-main">Gramicidin</span> Mix of ionophoric antibiotics

Gramicidin, also called gramicidin D, is a mix of ionophoric antibiotics, gramicidin A, B and C, which make up about 80%, 5%, and 15% of the mix, respectively. Each has 2 isoforms, so the mix has 6 different types of gramicidin molecules. They can be extracted from Brevibacillus brevis soil bacteria. Gramicidins are linear peptides with 15 amino acids. This is in contrast to unrelated gramicidin S, which is a cyclic peptide.

<span class="mw-page-title-main">Antimicrobial peptides</span> Class of peptides that have antimicrobial activity

Antimicrobial peptides (AMPs), also called host defence peptides (HDPs) are part of the innate immune response found among all classes of life. Fundamental differences exist between prokaryotic and eukaryotic cells that may represent targets for antimicrobial peptides. These peptides are potent, broad spectrum antimicrobials which demonstrate potential as novel therapeutic agents. Antimicrobial peptides have been demonstrated to kill Gram negative and Gram positive bacteria, enveloped viruses, fungi and even transformed or cancerous cells. Unlike the majority of conventional antibiotics it appears that antimicrobial peptides frequently destabilize biological membranes, can form transmembrane channels, and may also have the ability to enhance immunity by functioning as immunomodulators.

<span class="mw-page-title-main">Microcin</span> Class of very small bacterially produced peptide antibiotics

Microcins are very small bacteriocins, composed of relatively few amino acids. For this reason, they are distinct from their larger protein cousins. The classic example is microcin V, of Escherichia coli. Subtilosin A is another bacteriocin from Bacillus subtilis. The peptide has a cyclized backbone and forms three cross-links between the sulphurs of Cys13, Cys7 and Cys4 and the alpha-positions of Phe22, Thr28 and Phe31.

<span class="mw-page-title-main">Mutacin 1140</span> Chemical compound

Mutacin 1140 is a bacteriocin produced by Streptococcus mutans. It has activity against a broad spectrum of Gram-positive bacteria. It is a member of the class of compounds known as lantibiotics.

<span class="mw-page-title-main">Tyrocidine</span> Chemical compound

Tyrocidine is a mixture of cyclic decapeptides produced by the bacteria Brevibacillus brevis found in soil. It can be composed of 4 different amino acid sequences, giving tyrocidine A–D. Tyrocidine is the major constituent of tyrothricin, which also contains gramicidin. Tyrocidine was the first commercially available antibiotic, but has been found to be toxic toward human blood and reproductive cells. The function of tyrocidine within its host B. brevis is thought to be regulation of sporulation.

<span class="mw-page-title-main">Thienamycin</span> Chemical compound

Thienamycin is one of the most potent naturally produced antibiotics known thus far, discovered in Streptomyces cattleya in 1976. Thienamycin has excellent activity against both Gram-positive and Gram-negative bacteria and is resistant to bacterial β-lactamase enzymes. Thienamycin is a zwitterion at pH 7.

<span class="mw-page-title-main">Class II bacteriocin</span>

Class II bacteriocins are a class of small peptides that inhibit the growth of various bacteria.

<span class="mw-page-title-main">Thiostrepton</span> Chemical compound

Thiostrepton is a natural cyclic oligopeptide antibiotic of the thiopeptide class, derived from several strains of streptomycetes, such as Streptomyces azureus and Streptomyces laurentii. Thiostrepton is a natural product of the ribosomally synthesized and post-translationally modified peptide (RiPP) class.

<span class="mw-page-title-main">Bactoprenol</span> Chemical compound

Bactoprenol also known as dolichol-11 and C55-isoprenyl alcohol (C55-OH) is a lipid first identified in certain species of lactobacilli. It is a hydrophobic alcohol that plays a key role in the growth of cell walls (peptidoglycan) in Gram-positive bacteria.

Ribosomally synthesized and post-translationally modified peptides (RiPPs), also known as ribosomal natural products, are a diverse class of natural products of ribosomal origin. Consisting of more than 20 sub-classes, RiPPs are produced by a variety of organisms, including prokaryotes, eukaryotes, and archaea, and they possess a wide range of biological functions.

<span class="mw-page-title-main">Lipid II</span> Chemical compound

Lipid II is a precursor molecule in the synthesis of the cell wall of bacteria. It is a peptidoglycan, which is amphipathic and named for its bactoprenol hydrocarbon chain, which acts as a lipid anchor, embedding itself in the bacterial cell membrane. Lipid II must translocate across the cell membrane to deliver and incorporate its disaccharide-pentapeptide "building block" into the peptidoglycan mesh. Lipid II is the target of several antibiotics.

Mycofactocin (MFT) is a family of small molecules derived from a peptide of the type known as RiPP (ribosomally synthesized and post-translationally modified peptides), naturally occurring in many types of Mycobacterium. It was discovered in a bioinformatics study in 2011. All mycofactocins share a precursor in the form of premycofactocin (PMFT); they differ by the cellulose tail added. Being redox active, both PMFT and MFT have an oxidized dione (mycofactocinone) form and a reduced diol (mycofactocinol) form, respectively termed PMFTH2 and MFTH2.

Heike Brötz-Oesterhelt is a German microbiologist. She is a full professor and holds the Chair of the Department for Microbial Bioactive Compounds at the Interfaculty Institute for Microbiology and Infection Medicine, University of Tübingen, Germany.

<span class="mw-page-title-main">Cinnamycin</span> Cinnamycin is a type B lantibiotic produced by Streptomyces cinnamoneus

Cinnamycin is a tetracyclic antibacterial peptide produced by Streptomyces cinnamoneus containing 19 amino acid residues including the unusual amino acids threo-3-methyl-lanthionine, meso-lanthionine, lysinoalanine, and 3-hydroxyaspartic acid.

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. 1 2 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. 1 2 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.
  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. 1 2 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.
  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. 1 2 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.
  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.
  19. ↑ "DBT Centre for Bioinformatics Presidency University, Kolkata". Archived from the original on 2013-08-15. Retrieved 2013-07-25.

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