Teixobactin /ˌteɪks.oʊ.ˈbæk.tɪn/ is a small molecule antibiotic that is active against gram-positive bacteria. It appears to belong to a new 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 or Mycobacterium tuberculosis without the bacteria developing a resistance to the antibiotic.
Contents
[]
- 1History
- 2Biosynthesis
- 3Antibacterial activity
- 4Clinical research
- 5Intellectual property
- 6See also
- 7References
- 8External links
History[edit]
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 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.[7]
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.[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]
Biosynthesis[edit]
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 [[https://en.wikipedia.org/wiki/Amino_acid#Isomerism|D-amino acids]], a methylated phenylalanine, and the non-proteinogenic amino acid enduracididine. The amino acid sequence of teixobactin is MeHN—d-Phe—Ile—Ser——d-Gln—d-Ile—Ile—Ser—d-Thr*—Ala—enduracididine—Ile—COO—*. The carboxy terminus forms a lactone with the l-threonine residue (indicated by the asterisk), as is common in microbial nonribosomal peptides. This lactone-forming 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[edit]
Mechanism of action[edit]
Teixobactin is an inhibitor of cell wall synthesis. It acts primarily by binding to lipid II, a precursor to peptidoglycan. Lipid II is also targeted by the antibiotic vancomycin. Binding of teixobactin to lipid precursors inhibits production of the peptidoglycan layer, leading to lysis of vulnerable bacteria.[1]
Activity[edit]
Teixobactin was reported to be potent in vitro against all gram-positive bacteria tested, including Staphylococcus aureus and difficult-to-treat enterococci, with Clostridium difficile and Bacillus anthracis being exceptionally vulnerable. It also killed Mycobacterium tuberculosis. 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 PD50dose 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).[9]
Induction of resistance[edit]
No resistant strain of S. aureus or 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.[11][12] 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.[13]
Clinical research[edit]
In early 2015, human clinical trials of teixobactin were predicted 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.[14] 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.
Intellectual property[edit]
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 Universityholds 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 rights to patent any useful chemicals identified.[15] Kim Lewis, the lead author of the article in //Nature//, is a founder and paid consultant to this company.[5]
See also[edit]
Wikimedia Commons has media related to Teixobactin.
References[edit]
- ^ Jump up to://**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. 517: 455–9. doi:10.1038/nature14098. PMID 25561178.
- ^ Jump up to://**a**// //**b**// Wright, Gerard (7 January 2015). "Antibiotics: An irresistible newcomer". Nature. 517: 442–444. doi:10.1038/nature14193. PMID 25561172.
- ^ Jump up to://**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.
- ^ Jump up to://**a**// //**b**// //**c**// Gallagher, James (7 January 2015). "Antibiotics: US discovery labelled 'game-changer' for medicine". BBC. Retrieved 7 January2015.
- ^ Jump up to://**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 January2015.
- Jump up^ 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
Freely accessible. PMID 20173072. - Jump up^ Khatchadourian, Raffi (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.
- Jump up^ 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.
- ^ Jump up to://**a**// //**b**// Judy Stone (8 January 2015). "Teixobactin And iChip Promise Hope Against Antibiotic Resistance". Forbes. Retrieved 10 January2015.
- Jump up^ Sample, Ian (8 January 2015). "New class of antibiotic could turn the tables in battle against superbugs". The Guardian. Retrieved 11 January 2015.
- Jump up^ Azvolinsky, Anna. "New Antibiotic from Soil Bacteria". The Scientist. Retrieved 2 July 2015.
- Jump up^ Gallagher, James. "Antibiotics: U.S. discovery labeled "game-changer" for medicine". BBC News. Retrieved 2 July 2015.
- Jump up^ Arias CA, Murray BE (2015). "A new antibiotic and the evolution of resistance". The New England Journal of Medicine. 372 (12): 1168–70. doi:10.1056/NEJMcibr1500292. PMC 4433155 Freely accessible. PMID 25785976.
- Jump up^ Grant, Kelly (7 January 2015). "Newly discovered antibiotic shows promise in fight against superbugs". The Globe and Mail. Toronto. Retrieved 7 January 2015.
- Jump up^ WO 2014089053, "Novel depsipeptide and uses thereof", published 12 June 2014, assigned to Novobiotic Pharmaceuticals LLC [US]
External links[edit]
- Dr. Kim Lewis, Northeastern University, speaks about Teixobactin during his seminar at the NIH entitled "New antibiotics from the microbial dark matter. February 15, 2017
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https://phys.org/news/2017-11-scientists-significant-breakthrough-road-superbug-killing.html
Scientists make significant breakthrough on road to new superbug-killing antibiotic teixobactin
November 6, 2017
MRSAMethicillin-resistant Staphylococcus aureus. Credit: NIH/NIAID
Scientists working to develop a 'game-changing' new antibiotic have made a significant advance towards creating commercially viable drug treatments by producing two simplified synthetic versions of the substance which are just as potent at killing superbugs like MRSA as its natural form.
The breakthrough by researchers at the University of Lincoln, UK, marks another important step to realising the potential of teixobactin in aiding the global fight against antibiotic-resistant pathogens. Teixobactin is a recently discovered natural antibiotic which many in the international scientific community believe could lead to creation of the first commercially viable new antibiotic drug in 30 years.
The Lincoln team has successfully synthesized new simplified versions of teixobactin which harness the same powerful antibiotic effects in a way that could be produced on a commercial scale. Their findings are published in the Royal Society of Chemistry's journal, Chemical Science.
Until now, scientists attempting to synthesise teixobactin believed they needed to use cationic (or positively charged) amino acids which bind to the bacterial target using a 'side chain'. This meant they had to use either the very rare amino acid found naturally in teixobactin, called enduracididine, or alternative ones which had lower potency against superbugs.
Each amino acid sits at a specific place in teixobactin's structure, and the Lincoln team has now successfully replaced enduracididine – which holds position ten – with two alternative amino acids which are not positively charged. These amino acids lack the 'binding' part, over-turning the prior understanding that enduracididine is essential for to so-called 'target binding' to be highly potent against superbugs.
With this new knowledge, synthesised versions of teixobactin can be more easily developed, taking the process from up to 30 hours to just ten minutes for a single coupling step – a significant step towards turning teixobactin into a viable new drug. Importantly, the two new simplified forms of teixobactin have also proven to have identical potency against superbugs as the natural form of teixobactin.
Dr Ishwar Singh, a specialist in novel drug design and development from the University of Lincoln's School of Pharmacy, is leading the research team. He explained: "When teixobactin was discovered it was ground breaking in itself as a new antibiotic which kills bacteria without detectable resistance including superbugs such as MRSA. We have been investigating a way to simplify the design while retaining the high potency against resistant bacteria such as MRSA.
"This simplified design and more efficient synthesise will enable work to be carried out at a commercial level. Enduracididine was severely limiting our ability to do this because of its scarcity, a complex multistep synthesis, and long and repetitive steps of between 16 and 30 hours with high failure rate and very low yields.
"We needed to make a change to the structure so that we could make the molecule more viable for drug development. We had tried replacing it with other amino acids with a similar make up, but they all were less potent in comparison to the natural form ofteixobactin. Now, we have discovered that we can in fact use amino acids which are structurally different, and are commercially-available. They are also 16 times more potent than a clinically-used antibiotic in killing the superbug MRSA, and they were also highly potent against other antibiotic-resistant infections, such as vancomycin resistant enterococci, and tuberculosis."
The work builds on the success of the team's pioneering research to tackle antimicrobial resistance over the past 18 months. Dr Singh is working with colleagues from the School of Life Sciences and the School of Chemistry at the University of Lincoln to develop teixobactins into a viable drug.
Researchers predict that by 2050, an additional 10 million people will succumb to drug resistant infections each year. The development of new antibiotics which can be used as a last resort when other drugs are ineffective is therefore a crucial area of study for healthcare researchers around the world.
Explore further: Scientists move closer to defeating 'superbugs' with simplified forms of teixobactin
More information: Anish Parmar et al. Teixobactin analogues reveal enduracididine to be non-essential for highly potent antibacterial activity and lipid II binding, Chem. Sci. (2017). DOI: 10.1039/C7SC03241B
Read more at: https://phys.org/news/2017-11-scientists-significant-breakthrough-road-superbug-killing.html#jCp
Teixobactin analogues reveal enduracididine to be non-essential for highly potent antibacterial activity and lipid II binding
Anish Parmar,a Abhishek Iyer,ab Stephen H. Prior,c Daniel G. Lloyd,d Eunice Tze Leng Goh,e Charlotte S. Vincent,d Timea Palmai-Pallag,d Csanad Z. Bachrati,d Eefjan Breukink,f Annemieke Madder,b Rajamani Lakshminarayanan,e Edward J. Taylord and Ishwar Singh*a Author affiliations
Abstract
Teixobactin is a highly promising antibacterial depsipeptide consisting of four D-amino acids and a rare L-allo-enduracididine amino acid. L-allo-Enduracididine is reported to be important for the highly potent antibacterial activity of teixobactin. However, it is also a key limiting factor in the development of potent teixobactin analogues due to several synthetic challenges such as it is not commercially available, requires a multistep synthesis, long and repetitive couplings (16–30 hours). Due to all these challenges, the total synthesis of teixobactin is laborious and low yielding (3.3%). In this work, we have identified a unique design and developed a rapid synthesis (10 min μwave assisted coupling per amino acid, 30 min cyclisation) of several highly potent analogues of teixobactin with yields of 10–24% by replacing the L-allo-enduracididine with commercially available non-polar residues such as leucine and isoleucine. Most importantly, the Leu10-teixobactin and Ile10-teixobactin analogues have shown highly potent antibacterial activity against a broader panel of MRSA and Enterococcus faecalis(VRE). Furthermore, these synthetic analogues displayed identical antibacterial activity to natural teixobactin (MIC 0.25 μg mL−1) against MRSA ATCC 33591 despite their simpler design and ease of synthesis. We have confirmed lipid II binding and measured the binding affinities of individual amino acid residues of Ala10-teixobactin towards geranyl pyrophosphate by NMR to understand the nature and strength of binding interactions. Contrary to current understanding, we have shown that a cationic amino acid at position 10 is not essential for target (lipid II) binding and potent antibacterial activity of teixobactin. We thus provide strong evidence contrary to the many assumptions made about the mechanism of action of this exciting new antibiotic. Introduction of a non-cationic residue at position 10 allows for tremendous diversification in the design and synthesis of highly potent teixobactin analogues and lays the foundations for the development of teixobactin analogues as new drug-like molecules to target MRSA and Mycobacterium tuberculosis.
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