Teixobactin
A soil-bacterium depsipeptide discovered in 2015 that binds two different cell wall precursors at once and has so far failed to select for resistance in the laboratory — still entirely preclinical.
Also known as iChip-derived depsipeptide, Eleftheria terrae antibiotic
Animal data only — Rodent or other animal studies. Dose translation to humans is genuinely uncertain.
Teixobactin was published in Nature in 2015 by Ling and colleagues and generated enormous attention for the claim that no resistant mutants could be selected. That finding has held up, and the mechanism has been refined by later structural work. But more than a decade on, teixobactin has still not entered human trials — solubility, synthesis of the enduracididine residue and formulation remain unsolved. Treat it as an important scientific result and a promising scaffold, not as an available antibiotic.
How it works
Teixobactin was isolated from Eleftheria terrae, a previously uncultured soil beta-proteobacterium grown using the iChip in-situ diffusion device. It binds a highly conserved pyrophosphate-N-acetylglucosamine motif shared by lipid II (the peptidoglycan precursor) and lipid III (the wall teichoic acid precursor). Because the target is a non-protein, evolutionarily constrained lipid intermediate rather than an enzyme, mutational escape is difficult — 27-day serial passage of S. aureus and M. tuberculosis produced no resistant mutants, an unusual result. Later work showed teixobactin does more than sequester: it forms supramolecular fibrils on the membrane surface that concentrate the drug and cause additional membrane damage, a two-pronged attack on the cell envelope. Activity is strictly gram-positive because it cannot cross the gram-negative outer membrane. Development has been slowed by poor aqueous solubility, aggregation, and the synthetic difficulty of the rare L-allo-enduracididine residue, which has driven a large body of analogue chemistry.
Targets: Lipid II, Lipid III, Wall teichoic acid synthesis, Bacterial cell membrane
Dosing
| Protocol | Dose | Frequency | Route |
|---|---|---|---|
| Preclinical mouse efficacy dosingLaboratory use only. | — | single or repeated dosing in study protocols | intravenous |
- · Published mouse septicaemia and thigh infection studies used intravenous doses in the range of 1-20 mg/kg. There is no human dose, no human formulation and no clinical trial. Anyone selling teixobactin with a dosing protocol is selling a research chemical with a fictional label.
Cycling
Not applicable. Teixobactin has never been given to a human being in a clinical trial.
Pharmacology
- Half-life
- Not established in humans. Rodent studies show rapid clearance, and no human pharmacokinetic data exist.
- Onset
- Bactericidal within hours in vitro and in mouse infection models. No human onset data exist.
- Routes
- intravenous
- Molecule
- Natural-product macrocyclic depsipeptide, 11 residues including the rare amino acid enduracididine
- Sequence length
- 11 amino acids
- Molecular weight
- 1242.5 Da
Handling
- Diluent
- DMSO or dilute aqueous buffer for research use
- Lyophilised
- Freezer at -20°C or below, desiccated.
- Reconstituted
- Aliquot and freeze; avoid repeated freeze-thaw cycles.
Mixing
Native teixobactin has poor aqueous solubility and aggregates readily, which is one of the main barriers to formulation. Most laboratory work uses DMSO stocks diluted into buffer immediately before use.
Side effects
- rareUnknown in humans— No human exposure has been reported. Mouse studies found no obvious toxicity at effective doses and low haemolytic activity in vitro, but that is not a human safety profile.
Do not use if
- All human use — teixobactin is a preclinical compound with no human safety, pharmacokinetic or efficacy data whatsoever.
- No activity against gram-negative bacteria, so it would never be appropriate as empirical monotherapy even if it were available.
Combining it
- synergyvancomycin — Both target lipid II but at different sites, and teixobactin retains activity against vancomycin-resistant enterococci. Any combination work is purely in vitro.
- redundantnisin — Both are lipid II binders from the natural-product world, with overlapping gram-positive spectra.
What to monitor
- · Not applicable — there is no human use to monitor.
Legal status
Not approved anywhere and not in clinical trials. Available only as a research chemical.
References
- Ling et al. 2015, a new antibiotic kills pathogens without detectable resistance, Nature (preclinical)
- Shukla et al. 2022, teixobactin kills bacteria by a two-pronged attack on the cell envelope, Nature (preclinical)
- Reviews of teixobactin analogue synthesis and structure-activity relationships (review)
Mechanism in depth
Discovered in 2015 by culturing previously uncultivable soil bacteria in situ with the iChip. It binds lipid II and lipid III - the precursors of peptidoglycan and of wall teichoic acid - rather than a protein. Because the targets are conserved lipid intermediates and not gene products, resistance would require altering the cell wall chemistry itself, and none was detectable in the original laboratory selection experiments.
What usually goes wrong
The claim that gets overstated is 'resistance-free'. What the original work showed is that resistance did not arise under specific laboratory conditions over a defined period, which is a meaningful result and not the same claim. It also has no Gram-negative activity, because it cannot cross the outer membrane.
Receptor targets
- Lipid II and lipid III — High, to conserved lipid precursors
Blocks peptidoglycan and teichoic acid synthesis simultaneously
What to expect, and when
Not applicable - no human data.
Genuinely uncertain
- Still preclinical a decade after discovery; synthesis is difficult and no clinical trial has been completed.
- The durability of the low-resistance finding outside laboratory conditions is untested.