teixobactin

Teixobactin is a naturally occurring cyclic undecapeptide antibiotic, classified as a cyclic depsipeptide containing the unusual amino acid enduracididine, originally isolated from the soil bacterium Eleftheria terrae using the iChip cultivation platform. It represents a new class of antibiotics with potent bactericidal activity against a broad range of Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), Streptococcus pneumoniae, Clostridioides difficile, Bacillus anthracis, and Mycobacterium tuberculosis, while lacking significant activity against most Gram-negative bacteria due to their outer membrane barrier.[3][5][7][9] At the molecular level, teixobactin inhibits bacterial cell wall synthesis by binding with high affinity to conserved non-peptidic motifs in lipid II (the peptidoglycan precursor) and lipid III (the wall teichoic acid precursor), sequestering these undecaprenyl pyrophosphate–linked intermediates and blocking both peptidoglycan and wall teichoic acid biosynthetic pathways.[1][3][5][7][9][10] Structural and biophysical studies show that upon binding lipid II, teixobactin molecules assemble into antiparallel β-sheets and supramolecular fibrils at the membrane surface, forming large lipid II–teixobactin clusters that displace phospholipids, disrupt membrane organization, and cause membrane depolarization and leakage, providing a second, membrane-damaging component to its killing mechanism.[1][2][4][6][8] Because it targets highly conserved lipid precursors rather than mutable protein enzymes, teixobactin has shown no detectable emergence of resistance in vitro after prolonged sublethal exposure of Staphylococcus aureus or Mycobacterium tuberculosis, and it has demonstrated favorable efficacy and tolerability in multiple mouse infection models, making it a leading template for next-generation antibiotic development.[3][5][7][9][12]