Teixobactin: Difference between revisions
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== History == |
== History == |
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In January 2015 a collaboration of four institutes in the U.S. and Germany together with two [[pharmaceutical companies]], reported that they had isolated and characterized a new antibiotic, killing "without detectable resistance".<ref name="nature">{{vcite2 journal | vauthors = Ling LL, Schneider T, Peoples AJ, Spoering AL, Engels I, Conlon BP, Mueller A, Schäberle TF, Hughes DE, Epstein S, Jones M, Lazarides L, Steadman VA, Cohen DR, Felix CR, Fetterman KA, Millett WP, Nitti AG, Zullo AM, Chen C, Lewis K | title = A new antibiotic kills pathogens without detectable resistance | journal = [[Nature (journal)|Nature]] | volume = | issue = | date = 7 January 2015 | pmid = 25561178 | doi = 10.1038/nature14098 }}</ref><ref name="nature2">{{cite journal | first1=Gerard| last1=Wright| title = Antibiotics: An irresistible newcomer | journal = [[Nature (journal)|Nature]] | volume = | issue = | date = 7 January 2015 | pmid = | doi = 10.1038/nature14193 }}</ref><ref name="NovoBiotic">{{cite news| last=Lewis| first=Kim| date=7 January 2015 |title=NovoBiotic reports the discovery of teixobactin, a new antibiotic without detectable resistance| url = http://static.squarespace.com/static/54878590e4b0b8980d215324/t/54ad7aaae4b09209a6148464/1420655274323/2015+january+7th+Novobiotic+press+release.pdf| publisher=[[NovoBiotic Pharmaceuticals]]| location= [[Cambridge, Massachusetts]] |accessdate=7 January 2015 }}</ref><ref name="bbc">{{cite news |last=Gallagher |first=James |date=7 January 2015 |title=Antibiotics: US discovery labelled 'game-changer' for medicine |url=http://www.bbc.com/news/health-30657486 |newspaper=BBC |location= |accessdate=7 January 2015 }}</ref><ref name=NYT>{{cite web |last1=Denise |first1=Grady |title=From a pile of dirt, hope for a powerful new antibiotic |url=http://www.nytimes.com/2015/01/08/health/from-a-pile-of-dirt-hope-for-a-powerful-new-antibiotic.html |work=The New York Times |date=7 January 2015 |accessdate=7 January 2015 }}</ref> |
In January 2015 a collaboration of four institutes in the U.S. and Germany together with two [[pharmaceutical companies]], reported that they had isolated and characterized a new antibiotic, killing "without detectable resistance".<ref name="nature">{{vcite2 journal | vauthors = Ling LL, Schneider T, Peoples AJ, Spoering AL, Engels I, Conlon BP, Mueller A, Schäberle TF, Hughes DE, Epstein S, Jones M, Lazarides L, Steadman VA, Cohen DR, Felix CR, Fetterman KA, Millett WP, Nitti AG, Zullo AM, Chen C, Lewis K | title = A new antibiotic kills pathogens without detectable resistance | journal = [[Nature (journal)|Nature]] | volume = | issue = | date = 7 January 2015 | pmid = 25561178 | doi = 10.1038/nature14098 }}</ref><ref name="nature2">{{cite journal | first1=Gerard| last1=Wright| title = Antibiotics: An irresistible newcomer | journal = [[Nature (journal)|Nature]] | volume = | issue = | date = 7 January 2015 | pmid = | doi = 10.1038/nature14193 }}</ref><ref name="NovoBiotic">{{cite news| last=Lewis| first=Kim| date=7 January 2015 |title=NovoBiotic reports the discovery of teixobactin, a new antibiotic without detectable resistance| url = http://static.squarespace.com/static/54878590e4b0b8980d215324/t/54ad7aaae4b09209a6148464/1420655274323/2015+january+7th+Novobiotic+press+release.pdf| publisher=[[NovoBiotic Pharmaceuticals]]| location= [[Cambridge, Massachusetts]] |accessdate=7 January 2015 }}</ref><ref name="bbc">{{cite news |last=Gallagher |first=James |date=7 January 2015 |title=Antibiotics: US discovery labelled 'game-changer' for medicine |url=http://www.bbc.com/news/health-30657486 |newspaper=BBC |location= |accessdate=7 January 2015 }}</ref><ref name=NYT>{{cite web |last1=Denise |first1=Grady |title=From a pile of dirt, hope for a powerful new antibiotic |url=http://www.nytimes.com/2015/01/08/health/from-a-pile-of-dirt-hope-for-a-powerful-new-antibiotic.html |work=The New York Times |date=7 January 2015 |accessdate=7 January 2015 }}</ref> |
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Teixobactin was discovered by screening previously unculturable bacteria present in a sample of soil from “a grassy field in [[Maine]]”,<ref name="NYT"/> using the iChip (isolation chip).<ref name="pmid20173072">{{vcite2 journal | vauthors = Nichols D, Cahoon N, Trakhtenberg EM, Pham L, Mehta A, Belanger A, Kanigan T, Lewis K, Epstein SS | title = Use of ichip for high-throughput in situ cultivation of "uncultivable" microbial species | journal = Appl. Environ. Microbiol. | volume = 76 | issue = 8 | pages = 2445–50 | year = 2010 | pmid = 20173072 | pmc = 2849220 | doi = 10.1128/AEM.01754-09 }}</ref> 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. Tests for antibacterial activity against ''[[Staphylococcus aureus]]'' highlighted a previously undescribed bacterium which was named ''[[Eleftheria terrae]]''. It was found to be producing a new antibiotic compound that the researchers named teixobactin.<ref name="nature"></ref> Its absolute [[stereochemistry]] was determined employing techniques that included [[chemical degradation]] with advanced Marfey’s analysis as well as partial degradation, synthesis of fragments obtained by degradation and the synthesis of all four [[diastereomer]]s of an unusual [[amino acid]] not occurring in [[protein]]s.<ref name="Selcia">{{cite news| last=Matthews| first=Andy| date=8 January 2015 |title=Selcia Scientists Elucidate Stereochemistry of Novel Antibacterial Macrocycle Teixobactin, Published in Nature| url = http://www.selcia.com/news/selcia-scientists-elucidate-stereochemistry-novel-antibacterial-macrocycle-teixobactin| publisher=[[Selcia]]| location= [[Essex]], U.K.| accessdate=10 January 2015 }}</ref> Teixobactin is the first novel antibiotic with drug potential isolated from bacteria in decades, and appears to represent a new [[Antibiotics#Classes|class of antibiotics]], raising hopes that the new isolation techniques employed could lead to further antibiotic discoveries. |
Teixobactin was discovered by screening previously unculturable bacteria present in a sample of soil from “a grassy field in [[Maine]]”,<ref name="NYT"/> using the iChip (isolation chip).<ref name="pmid20173072">{{vcite2 journal | vauthors = Nichols D, Cahoon N, Trakhtenberg EM, Pham L, Mehta A, Belanger A, Kanigan T, Lewis K, Epstein SS | title = Use of ichip for high-throughput in situ cultivation of "uncultivable" microbial species | journal = Appl. Environ. Microbiol. | volume = 76 | issue = 8 | pages = 2445–50 | year = 2010 | pmid = 20173072 | pmc = 2849220 | doi = 10.1128/AEM.01754-09 }}</ref> 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. Tests for antibacterial activity against ''[[Staphylococcus aureus]]'' highlighted a previously undescribed bacterium which was named ''[[Eleftheria terrae]]''. It was found to be producing a new antibiotic compound that the researchers named teixobactin.<ref name="nature"></ref> Its absolute [[stereochemistry]] was determined employing techniques that included [[chemical degradation]] with advanced Marfey’s analysis as well as partial degradation, synthesis of fragments obtained by degradation and the synthesis of all four [[diastereomer]]s of an unusual [[amino acid]] not occurring in [[protein]]s.<ref name="Selcia">{{cite news| last=Matthews| first=Andy| date=8 January 2015 |title=Selcia Scientists Elucidate Stereochemistry of Novel Antibacterial Macrocycle Teixobactin, Published in Nature| url = http://www.selcia.com/news/selcia-scientists-elucidate-stereochemistry-novel-antibacterial-macrocycle-teixobactin| publisher=[[Selcia]]| location= [[Essex]], U.K.| accessdate=10 January 2015 }}</ref> Teixobactin is the first novel antibiotic with drug potential isolated from bacteria in decades, and appears to represent a new [[Antibiotics#Classes|class of antibiotics]], raising hopes that the new isolation techniques employed could lead to further antibiotic discoveries.<ref name=nature2/><ref name=bbc/><ref name=forbes/><ref name="guardian">{{cite news |last=Sample|first=Ian|date=8 January 2015 |title=New class of antibiotic could turn the tables in battle against superbugs|url=http://www.theguardian.com/science/2015/jan/07/antibiotic-drug-resistance-teixobactin |newspaper=The Guardian |location= |accessdate=11 January 2015 }}</ref> |
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== Biosynthesis == |
== Biosynthesis == |
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Revision as of 16:25, 12 January 2015
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| Identifiers | |
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3D model (JSmol)
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| ChemSpider | |
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| Properties | |
| C 58H 95N 15O 15 | |
| Molar mass | 1242 g/mol |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Teixobactin is an antibiotic which is active against Gram-positive bacteria that have developed resistance to available approved antibiotics. The discovery was reported in January 2015. The antibiotic was found in a screen of soil bacteria grown in a diffusion culture chamber that exposed previously unculturable bacteria to ambient nutrients and growth factors from the soil of origin.
History
In January 2015 a collaboration of four institutes in the U.S. 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 iChip (isolation chip).[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. Tests for antibacterial activity against Staphylococcus aureus highlighted a previously undescribed bacterium which was named Eleftheria terrae. It was found to be producing a new antibiotic compound that the researchers named teixobactin.[1] Its absolute stereochemistry was determined employing techniques that included 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.[7] Teixobactin is the first novel antibiotic with drug potential isolated from bacteria in decades, and appears to represent a new class of antibiotics, raising hopes that the new isolation techniques employed could lead to further antibiotic discoveries.[2][4][8][9]
Biosynthesis
Teixobactin is an 11-residue, macrocyclic depsipeptide hypothesized by its discoverers to be synthesized in E. terrae by the nonribosomal peptide synthetases Txo1 and Txo2 (encoded by the genes txo1 and txo2). [1] The peptide has several unusual features, including four D-amino acids, a methylated phenylalanine, and the non-proteinogenic amino acid enduracididine. 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. Ring closure between threonine and the last isoleucine is catalyzed by two C-terminal thioesterase domains of Txo2, forming a lactone.[1]
Antibacterial activity
Mechanism of action
Teixobactin is an inhibitor of cell wall synthesis that acts primarily by binding to lipid II, a fatty molecule which is a precursor to peptidoglycan. This is similar to the action of the antibiotic vancomycin. Binding of teixobactin to lipid precursors inhibits production of the peptidoglycan layer, leading to lysis of vulnerable bacteria.[1]
Activity
Teixobactin was reported to be potent in vitro against most Gram positive bacteria, including S. aureus and difficult-to-treat enterococci and M. tuberculosis, with Clostridium difficile and Bacillus anthracis being exceptionally vulnerable. It was also found to be effective in vivo, when used to treat mice infected with methicillin-resistant S. aureus (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 outer membrane such as gram negative pathogens, particularly carbapenem resistant enterobacteriaceae, or those with New Delhi metallo-beta-lactamase 1 (NDM1).[8]
Induction of resistance
No resistant strain of Staphylococcus aureus or Mycobacterium 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]
Clinical research
In early 2015, human clinical trials of teixobactin were estimated to be at least two years away. One co-discoverer estimated a drug development cost "in the low $100-millions" on a five to six year schedule. Pharmaceutical companies have been reluctant to make such investments in new antibiotics, because their wide prescription is likely to be discouraged in order to retard development of resistance, which has come to be considered almost inevitable.[10]
Intellectual property
The research was funded by the National Institutes of Health and German research agencies (some co-authors are based at the University of Bonn). Northeastern University holds a patent on the iChip method of culturing and isolating bacteria in situ in soil, and licensed this patent to a privately held company, NovoBiotic Pharmaceuticals, in Cambridge, Massachusetts, which owns the patent rights to any compounds produced.[11] Kim Lewis, the lead author of the article in Nature, is a founder and paid consultant to this company.[5]
See also
References
- ^ a b c d e f g Ling LL, Schneider T, Peoples AJ, Spoering AL, Engels I, Conlon BP, Mueller A, Schäberle TF, Hughes DE, Epstein S, Jones M, Lazarides L, Steadman VA, Cohen DR, Felix CR, Fetterman KA, Millett WP, Nitti AG, Zullo AM, Chen C, Lewis K (7 January 2015). "A new antibiotic kills pathogens without detectable resistance". Nature. doi:10.1038/nature14098. PMID 25561178.
- ^ a b Wright, Gerard (7 January 2015). "Antibiotics: An irresistible newcomer". Nature. doi:10.1038/nature14193.
- ^ a b Lewis, Kim (7 January 2015). "NovoBiotic reports the discovery of teixobactin, a new antibiotic without detectable resistance" (PDF). Cambridge, Massachusetts: NovoBiotic Pharmaceuticals. Retrieved 7 January 2015.
- ^ a b c Gallagher, James (7 January 2015). "Antibiotics: US discovery labelled 'game-changer' for medicine". BBC. Retrieved 7 January 2015.
- ^ a b c Denise, Grady (7 January 2015). "From a pile of dirt, hope for a powerful new antibiotic". The New York Times. Retrieved 7 January 2015.
- ^ Nichols D, Cahoon N, Trakhtenberg EM, Pham L, Mehta A, Belanger A, Kanigan T, Lewis K, Epstein SS (2010). "Use of ichip for high-throughput in situ cultivation of "uncultivable" microbial species". Appl. Environ. Microbiol. 76 (8): 2445–50. doi:10.1128/AEM.01754-09. PMC 2849220. PMID 20173072.
- ^ Matthews, Andy (8 January 2015). "Selcia Scientists Elucidate Stereochemistry of Novel Antibacterial Macrocycle Teixobactin, Published in Nature". Essex, U.K.: Selcia. Retrieved 10 January 2015.
- ^ a b Judy Stone (8 January 2015). "Teixobactin And iChip Promise Hope Against Antibiotic Resistance". Forbes. Retrieved 10 January 2015.
- ^ Sample, Ian (8 January 2015). "New class of antibiotic could turn the tables in battle against superbugs". The Guardian. Retrieved 11 January 2015.
- ^ Grant, Kelly (7 January 2015). "Newly discovered antibiotic shows promise in fight against superbugs". The Globe and Mail. Toronto. Retrieved 7 January 2015.
- ^ WO 2014089053, "Novel depsipeptide and uses thereof", published 12 June 2014, assigned to Novobiotic Pharmaceuticals LLC [US]