Dual Targeting of Cell Wall Precursors by Teixobactin Leads to Cell Lysis

Abstract

Teixobactin represents the first member of a newly discovered class of antibiotics that act through inhibition of cell wall synthesis. Teixobactin binds multiple bactoprenol-coupled cell wall precursors, inhibiting both peptidoglycan and teichoic acid synthesis. Here, we show that the impressive bactericidal activity of teixobactin is due to the synergistic inhibition of both targets, resulting in cell wall damage, delocalization of autolysins, and subsequent cell lysis. We also find that teixobactin does not bind mature peptidoglycan, further increasing its activity at high cell densities and against vancomycin-intermediate Staphylococcus aureus (VISA) isolates with thickened peptidoglycan layers. These findings add to the attractiveness of teixobactin as a potential therapeutic agent for the treatment of infection caused by antibiotic-resistant Gram-positive pathogens.

Rational Design and Synthesis of Modified Teixobactin Analogues: In Vitro Antibacterial Activity against Staphylococcus aureus, Propionibacterium acnes and Pseudomonas aeruginosa

“…In contrast, most of the teixobactin analogues tested showed the same MIC across all the S. aureus strains, including Mu50. Hence, these teixobactin analogues, similar to the parent teixobactin, are unaffected by the thicker peptidoglycan layers in the VISA strains . On a side note, studies have suggested the addition of a surfactant in the broth microdilution assay to prevent possible adsorption of the peptide compounds to the plastic wall of the 96‐well plate .…”

“…Teixobactin offers a potential solution to this predicament because it remains effective against MRSA, as well as the vancomycin‐intermediate S. aureus (VISA) due to its unique mode of action . It has been shown to synergistically block the biosyntheses of peptidoglycan and teichoic acid, thereby resulting in a weakened cell wall and autolysin‐mediated cell lysis …”

X-ray crystallographic structure of a teixobactin analogue reveals key interactions of the teixobactin pharmacophore

“…1,2 In reflection of this promise, the initial report has been cited more than 500 times. Teixobactin is a non-ribosomal cyclic undecadepsipeptide and contains the rare amino acid allo -enduracididine at position 10.…”

Über bisherige Denkweisen hinaus – neue Wirkstoffe zur Überwindung der Antibiotika‐Krise

“…Lediglich E.-coli-Mutanten mit einer defekten äußeren Membran sind anfällig,was darauf hindeutet, dass das Antibiotikum die äußere Membran von Gram-negativen Bakterien nicht durchdringen kann. [145] Die fehlende Resistenzentwicklung ist somit auf den multiplen Wirkmechanismus zurückzuführen;zudem adressiert Te ixobactin ein hochkonserviertes Nicht-Protein-Target. Beispielsweise lag in einem Maus-Sepsismodell einer intraperitonealen MRSA-Infektion der PD 50 -Wert (schützende Dosis,bei der die Hälfte der Tiere überleben) fürT eixobactin bei 0.2 mg pro kg, während Va ncomycin einen PD 50 -Wert von 2.75 mg pro kg aufweist.…”