Teixobactin

Source: Wikipedia, the free encyclopedia.
Not to be confused with Tazobactam.
Teixobactin
Teixobactin skeleton
Clinical data
ATC code
  • none
Legal status
Legal status
  • In general: unscheduled
Pharmacokinetic data
BioavailabilityUnknown
Protein bindingUnknown
MetabolismUnknown
Onset of actionUnknown
Elimination half-lifeUnknown
ExcretionUnknown
Identifiers
  • (2R)-N-[(2R,3S)-1-[[(2S,3S)-1-[[(2S)-1-[[(3S,6S,9S,12R,13S)-6-[[(5S)-2-amino-4,5-dihydro-1H-imidazol-5-yl]methyl]-3-[(2S)-butan-2-yl]-9,13-dimethyl-2,5,8,11-tetraoxo-1-oxa-4,7,10-triazacyclotridec-12-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]-2-[[(2S)-3-hydroxy-2-[[(2S,3S)-3-methyl-2-[[(2R)-2-(methylamino)-3-phenylpropanoyl]amino]pentanoyl]amino]propanoyl]amino]pentanediamide
JSmol)
  • CC[C@H](C)[C@H]1C(=O)O[C@H]([C@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N1)C[C@H]2CNC(=N)N2)C)NC(=O)[C@H](CO)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H]([C@@H](C)CC)NC(=O)[C@@H](CCC(=O)N)NC(=O)[C@H](CO)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H](Cc3ccccc3)NC)C
  • InChI=1/C58H95N15O15/c1-12-28(5)42(70-49(79)37(61-11)23-34-19-17-16-18-20-34)53(83)67-39(26-74)51(81)65-36(21-22-41(59)76)48(78)69-44(30(7)14-3)55(85)71-43(29(6)13-2)54(84)68-40(27-75)52(82)73-46-33(10)88-57(87)45(31(8)15-4)72-50(80)38(24-35-25-62-58(60)64-35)66-47(77)32(9)63-56(46)86/h16-20,28-33,35-40,42-46,61,74-75H,12-15,21-27H2,1-11H3,(H2,59,76)(H,63,86)(H,65,81)(H,66,77)(H,67,83)(H,68,84)(H,69,78)(H,70,79)(H,71,85)(H,72,80)(H,73,82)(H3,60,62,64)/t28-,29-,30-,31-,32-,33-,35-,36+,37+,38-,39-,40-,42-,43-,44+,45-,46+/m0/s1

Teixobactin (

class of antibiotics, and harms bacteria by binding to lipid II and lipid III, important precursor molecules for forming the cell wall
.

Teixobactin was discovered using a new method of culturing bacteria in soil, which allowed researchers to grow a previously unculturable bacterium now named Eleftheria terrae, which produces the antibiotic. Teixobactin was shown to kill Staphylococcus aureus and Mycobacterium tuberculosis.

History

In January 2015, a collaboration of four institutes in the US and Germany together with two

pharmaceutical companies, reported that they had isolated and characterized a new antibiotic, killing "without detectable resistance."[1][2][3][4][5] Teixobactin was discovered by screening previously unculturable bacteria present in a sample of soil from "a grassy field in Maine,"[5] using the isolation chip (iChip).[6]

The multiple independent iChip culture cells in a block of plastic are inoculated with soil diluted to deposit about one bacterium in each cell, and then sealed with semi-permeable membranes. The iChip is then planted in a box of the soil of origin. Nutrients and growth factors diffusing from the ambient soil into each culture cell through the membranes nurture growth of the bacterium into a colony that is then self-sustaining in vitro. This arrangement allows growth of only one species in some of the cells.[7]

Tests for antibacterial activity against

chemical degradation with advanced Marfey's analysis as well as partial degradation, synthesis of fragments obtained by degradation and the synthesis of all four diastereomers of an unusual amino acid not occurring in proteins.[8]

Teixobactin is the first novel antibiotic with drug potential isolated from bacteria in decades. It appears to represent a new

class of antibiotics, raising hopes that the new isolation techniques employed could lead to further antibiotic discoveries.[2][4][9][10][11]

Biosynthesis

Teixobactin is an 11-residue,

ring closure reaction is catalyzed by two C-terminal thioesterase domains of Txo2, forming a lactone.[1] Txo1 and Txo2 are together composed of 11 modules, and each module is thought to sequentially add one amino acid to a growing peptide chain. The first module has a methyltransferase
domain that methylates the N-terminal phenylalanine.

Antibacterial activity

Mechanism of action

Teixobactin is an inhibitor of cell wall synthesis. It acts primarily by binding to lipid II, a precursor to peptidoglycan. In addition to inhibiting cell wall synthesis, teixobactin's capacity to form large supramolecular fibrils upon lipid II binding compromises the integrity of the bacterial membrane, contributing to the killing mechanism.[12] The incorporation of D- and L- amino acids enables allocating teixobactin's hydrophobic residues onto the bacterial membrane surface. [13] Lipid II is also targeted by the antibiotic vancomycin. The binding of teixobactin to lipid precursors inhibits the production of the peptidoglycan layer, leading to lysis of vulnerable bacteria.[1]

Activity

Teixobactin was reported to be potent

MRSA), and Streptococcus pneumoniae. The dose required to achieve 50% survival against MRSA is only 10% of the PD50 dose of vancomycin, an antibiotic typically used for MRSA.[1]

It is not active against bacteria with an

carbapenem resistant enterobacteriaceae, or those with New Delhi metallo-beta-lactamase 1 (NDM1).[9]

Induction of resistance

No resistant strain of

M. tuberculosis was generated in vitro when administering sublethal doses, for as long as 27 days in the case of the former.[1][3] It is postulated that teixobactin is more robust against mutation of the target pathogens, because of its unusual antibiotic mechanism of binding to less mutable fatty molecules rather than binding to relatively mutable proteins in the bacterial cell.[4] However, several scientists caution that it is too early to conclude that teixobactin resistance would not develop in the clinical setting.[14][15] Similar claims were made for vancomycin, yet resistance emerged soon after large-scale use in the 1980s. It is possible that genes encoding resistance to teixobactin are already present in soil bacteria. Resistance could also arise by mutation after prolonged use in patients.[16]

Society and culture

NovoBiotic Pharmaceuticals has been issued two US patents on teixobactin (US Patents 9,163,065 and 9,402,878). Northeastern University, where Kim Lewis, the senior author of the article in Nature, works, filed a patent on the method used to discover teixobactin, and licensed it to NovoBiotic in 2003; Lewis is a consultant to the company.[5]

Research

In 2016 researchers synthesized the compound[17][18][19] and used it to treat a bacterial infection in mice.[20][11]

See also

Scholia has a profile for teixobactin (Q18720369).
Wikimedia Commons has media related to Teixobactin.

References

  1. ^
    PMID 25561178
    .
  2. ^
    S2CID 4464402
    .
  3. ^ a b Lewis K (7 January 2015). "NovoBiotic reports the discovery of teixobactin, a new antibiotic without detectable resistance" (PDF). Cambridge, Massachusetts: NovoBiotic Pharmaceuticals. Retrieved 7 January 2015.
  4. ^ a b c Gallagher J (7 January 2015). "Antibiotics: US discovery labelled 'game-changer' for medicine". BBC. Retrieved 7 January 2015.
  5. ^ a b c Denise G (7 January 2015). "From a pile of dirt, hope for a powerful new antibiotic". The New York Times. Retrieved 7 January 2015.
  6. PMID 20173072
    .
  7. ^ Khatchadourian R (20 June 2016). "The Unseen: Millions of microbes are yet to be discovered. Will one hold the ultimate cure?". The New Yorker. New York: Condé Nast. Retrieved 27 June 2016.
  8. ^ Matthews A (8 January 2015). "Selcia Scientists Elucidate Stereochemistry of Novel Antibacterial Macrocycle Teixobactin, Published in Nature". Essex, U.K.: Selcia. Retrieved 10 January 2015.
  9. ^ a b Stone J (8 January 2015). "Teixobactin And iChip Promise Hope Against Antibiotic Resistance". Forbes. Retrieved 10 January 2015.
  10. ^ Sample I (8 January 2015). "New class of antibiotic could turn the tables in battle against superbugs". The Guardian. Retrieved 11 January 2015.
  11. ^
    S2CID 219586005
    .
  12. PMID 35922513
    .
  13. PMID 32503964
    .
  14. ^ Azvolinsky A. "New Antibiotic from Soil Bacteria". The Scientist. Retrieved 2 July 2015.
  15. ^ Gallagher J (7 January 2015). "Antibiotics: U.S. discovery labeled "game-changer" for medicine". BBC News. Retrieved 2 July 2015.
  16. PMID 25785976
    .
  17. PMID 27484680
    .
  18. PMID 27191730
    .
  19. S2CID 208608523
    .
  20. ^ Haridy R (March 25, 2018). ""Game-changing" synthesized antibiotic successfully treats infections for the first time". newatlas.com. Retrieved 2018-04-03.

External links

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