Teixobactin kills bacteria by a two-pronged attack on the cell envelope

Area of Science:

• Biochemistry
• Microbiology
• Structural Biology

Background:

• Antimicrobial resistance necessitates novel antibiotics with unique mechanisms.
• Teixobactin is a new antibiotic class targeting lipid II, a peptidoglycan precursor.
• Existing membrane-acting antibiotics often exhibit toxicity to eukaryotic cells.

Purpose of the Study:

• To elucidate the atomic-level mechanism of teixobactin action.
• To understand how teixobactin overcomes antimicrobial resistance.
• To investigate teixobactin's selective toxicity towards bacterial membranes.

Main Methods:

• Solid-state NMR spectroscopy
• Microscopy techniques (including atomic force microscopy)
• In vivo assays
• Molecular dynamics simulations

Main Results:

• Teixobactin binds specifically to the pyrophosphate-sugar moiety of lipid II, forming a β-sheet supramolecular structure.
• This supramolecular assembly disrupts the bacterial membrane integrity by displacing phospholipids.
• Teixobactin demonstrates selective toxicity, targeting bacterial membranes containing lipid II, which are absent in eukaryotes.

Conclusions:

• The atomic-level understanding of teixobactin's mechanism reveals its dual action against cell wall synthesis and membrane integrity.
• Teixobactin's specific binding to lipid II explains its lack of resistance and selective toxicity.
• This structural knowledge facilitates the rational design of next-generation antibiotic drug candidates.