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

Abstract

The X-ray crystallographic structure of a truncated teixobactin analogue reveals hydrogen-bonding and hydrophobic interactions and a cavity that binds a chloride anion. Minimum inhibitory concentration (MIC) assays against Gram-positive bacteria correlate the observed structure with antibiotic activity.

Probing key elements of teixobactin–lipid II interactions in membranes

“…Based on Txb's substrate selectivity6 and proposed pharmacophore,15 Txb may bind lipid II at its head group. Then the most likely interactions would take place between the pyrophosphate of lipid II and the cyclodepsipeptide ring of Txb.…”

“…Most interactions have been interpreted based on the comparison of bacterial growth inhibition activities of numerous chemically synthesized Txb analogs 8–27. In particular, one of the inactive analogs, designated “Ac–Δ 1–5 –Arg 10 –Txb”,15 has been crystallized from solution as a hydrochloride salt, where the chloride anion is coordinated at the center of several backbone amides that form the C-terminal cyclodepsipeptide ring. The guanidinium group of the arginine side chain (which replaces the allo -End in wildtype Txb) also contributes to chloride binding.…”

“…As surmised from the chloride-bound crystal structure of this inactive Arg10-based analog, as well as the relative activities of other Txb analogs with single-residue substitutions, the binding of Txb to lipid II or other UPP derivatives is hypothesized to consist of two kinds of interactions: polar interactions that are primarily mediated by the cyclodepsipeptide ring, and hydrophobic interactions that are likely contributed by residues at the two termini 15. As the structure of the bona fide Txb–lipid II complex is yet to be determined, these hypothesized interactions remain to be elucidated.…”

“…As the structure of the bona fide Txb–lipid II complex is yet to be determined, these hypothesized interactions remain to be elucidated. Additionally, since the crystallized Txb analog strongly favors binding to a chloride anion rather than to an inorganic pyrophosphate,15 it is possible that some key interactions of Txb are not reproduced by the inactive analog, or that certain interactions can take place only at a membrane surface and not in aqueous solution.…”

Teixobactin and Its Analogues: A New Hope in Antibiotic Discovery

“…The direct 3D structural comparison of two important is essential and D-allo-Ile 5 is important to maintain the disordered structure. Very recently, Nowick and co-workers reported the X-ray crystallographic structure of a truncated teixobactin analogue 11 ( Figure 2C,D) in which the hydrophobic as well as the hydrogen bonding interactions present in the cavity structure containing a chloride ion were shown. Interestingly, the arginine residue of this truncated analogue provides a key interaction with the chloride ion via a folded conformation in the crystal structure ( Figure 2D).…”