The teixobactin molecule - rotatable in 3 dimensions
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Teixobactin has been hailed as one of the most promising recent biochemical developments: a new antibiotic, produced by a novel organism, Eleftheria terrae, isolated by following a new technique, which greatly expands the number of microbial species that may be investigated in the laboratory. It targets microbial cells in a different way than most antibiotics, and this seems less likely to be overtaken by the development of resistant bacterial strains. It is active against Gram positive bacteria e.g. Staphylococcus aureus - MRSA - and Enterococci as well as Mycobacterium tuberculosis - cause of TB - but not a range of other Gram negative bacteria.
It was announced in Nature in January 2015 and widely publicised in national newspapers.
However it has yet to undergo some years of testing before it is generally available.
StructureThe teixobactin molecule is composed of a chain of 11 amino acids, linked by 10 peptide linkages, with the last 4 looped into a square section:
N-methyl-D-phenylalanine, L-isoleucine, L-serine, D-glutamine, D-isoleucine, L-isoleucine, L-serine, D-threonine, L-alanine, L-enduracididine, D-isoleucine. Label amino acid residues.
At each end of the molecule are unusual substituted amino-acids: N-methyl-D-phenylalanine and L-enduracididine (not one of the usual amino acids in proteins - but similar to 2-amino-histidine). This means that the peptide chain does not have the usual end groups: -NH2 at the N-terminal end -COOH at the C-terminal end. In fact the N terminal end is methylated, and the C terminal end joins via an ester link back to threonine, forming a lactone. This makes the molecule a depsipeptide. Additionally, some of the amino acids are in the D-form rather than the usual L-form.
Mode of actionTeixobactin inhibits bacterial cell wall synthesis, primarily by binding to lipid II, a fatty molecule which is a precursor to peptidoglycan, as well as lipid III, precursor of teichoic acid, which projects from the Gram positive bacterial cell wall.
This is different from the action of the antibiotic vancomycin which binds with the terminal dipeptide D-alanyl-D-alanine of peptidoglycan precursors. Bacterial strains have gained resistance through producing different versions of this section. And of course it is different from the way that β-lactamase antibiotics, e.g. penicillin, interfere with cell wall formation after interacting with penicillin-binding proteins.
There is some similarity with other classes of antibiotics which also disrupt bacterial cell wall biosynthesis. Mannopeptimycins and Enduracidin also contain both D- and L-forms of enduracididine or its hydroxy form, and feature chains of amino acids with looped sections.
Related units available on this siteBackground to the discovery of teixobactin
Antibiotics (simple introduction)
Antibiotic types (not so simple)
Production of antibiotics
++ to come
Diseases caused by bacteria, with special reference to antibiotic resistance
Web referencesA new antibiotic kills pathogens without detectable resistance - a 21-author paper in Nature involving collaboration between workers in the USA, Germany and UK: at NovoBiotic Pharmaceuticals, Cambridge, Mass, University of Bonn Pharmaceutical Microbiology Section, Northeastern University, Boston, Mass, and Selcia, Ongar, Essex UK - Main source of information about teixobactin
Promising antibiotic discovered in microbial 'dark matter' Potential drug kills pathogens such as MRSA - and was discovered by mining 'unculturable' bacteria - a trailer for the above.
Teixobactin: Powerful New Antibiotic Kills Drug-Resistant Bacteria : a brief article but with good explanation of its mode of action
Teixobactin And iChip Promise Hope Against Antibiotic Resistance by Judy Stone, a quite well informed Contributor..
Teixobactin: A New Antibiotic From a New Platform? posted by Derek - a blogger on drug discovery and the pharma industry in general.
Incubation of environmental samples in a diffusion chamber increases the diversity of recovered isolates. (Bollmann A1, Lewis K, Epstein SS) - background information about (standard size) diffusion chamber.
Scientists Discover Potent Antibiotic, A Potential Weapon Against a Range of Diseases (Wall street Journal) - not sure about the Drug Quest graphic or the forum opinions.
The enduracidin biosynthetic gene cluster from Streptomyces fungicidicus : Enduracidin is a 17 aa peptide antibiotic (containing both D- and L-forms of enduracididine) which disrupts bacterial cell wall biosynthesis, but with a mechanism of action that is distinct from the β-lactams and vancomycin.
Mechanism of Action of the Mannopeptimycins, a Novel Class of Glycopeptide Antibiotics Active against Vancomycin-Resistant Gram-Positive Bacteria : The antimicrobial activities of several mannopeptimycin derivatives correlated with their affinities toward lipid II, suggesting that the inhibition of cell wall biosynthesis was primarily through lipid II binding. In addition, it was shown that mannopeptimycins bind to lipoteichoic acid in a rather nonspecific interaction, which might facilitate the accumulation of antibiotic on the bacterial cell surface.