The cyclic octapeptide antibiotic argyrin B inhibits translation by trapping EF-G on the ribosome during translocation

Abstract

Significance The increase in multidrug-resistant bacteria highlights the urgent need for compounds with novel target sites that can be developed as antibiotics. The argyrins represent a family of naturally produced octapeptides that display promising activity against Pseudomonas aeruginosa by inhibiting protein synthesis. Our structural and kinetic analyses reveal that argyrins inhibit protein synthesis by interacting with, and trapping, the translation elongation factor G (EF-G) on the ribosome, analogous to that reported previously for the unrelated antibiotic fusidic acid. However, the binding site of argyrin on EF-G is distinct from that of fusidic acid, indicating that intramolecular movements at the domain III/V interface of EF-G are also essential for facilitating late events in the translocation mechanism.

Gut colonization by Bacteroides requires translation by an EF‐G paralog lacking GTPase activity

“…Co‐sedimentation assays were performed as described (Cunha et al , 2013; Wieland et al , 2022). Specifically, 0.4 μM of purified E. coli 70S were mixed with 1 μM indicated EF‐G protein, 500 μM GTP in TAKM 7 buffer (50 mM Tris–HCl pH 7.5 at 37°C, 70 mM NH 4 Cl, 30 mM KCl and 7 mM MgCl 2 ).…”

Crystal structure of natural product argyrin-D determined by 3D electron diffraction

“…This could be utilized to improve restraints for the refinement of lower resolution structures such as that of a recently published complex of EF-G with ArgB and the E. coli 70S ribosome. 12 Here, despite a similar protein environment compared to the free EF-G/ ArgB complex, poor electron density around ArgB led to fitting of a distorted macrocycle, lacking internal hydrogen bonds that act as stabilizing forces.…”

“…As the new data suggest, ArgB does not prevent ribosome binding of EF-G but instead interacts with EF-G on ribosomes stalling the resulting complex at the translocation step. 12 Production of argyrins has been accomplished through both total synthesis 13 and biotechnological approaches. 14,15 While synthetic routes to argyrins offer flexibility towards the modification of individual amino acid residues, thereby facilitating medicinal chemistry studies, the biotechnological approach furnishes convenient and scalable production of natural, as well as non-natural argyrins.…”

“…As the new data suggest, ArgB does not prevent ribosome binding of EF-G but instead interacts with EF-G on ribosomes stalling the resulting complex at the translocation step. 12…”

One-Year Water-Stable and Porous Bi(III) Halide Semiconductor with Broad-Spectrum Antibacterial Performance

“…Therefore, there is immense interest in the scientific community in developing nextgeneration drug candidates with improved antibacterial efficiency, efficacy, and selectivity. 27−29 Current commercially available antibacterial compounds are based on either organic molecules (e.g., nitrofurazone (NZF), 30 ampicillin, 31 nitrofurantoin (NFT), 32 and argyrin 33 ) or inorganic complexes (e.g., silver (Ag(I)) 34 and bismuth (Bi(III) compounds)). 35 Interestingly, bacteria are quite competent in adopting mechanisms for degrading organic antibacterial agents.…”