Elfamycins: inhibitors of elongation factor-Tu

Abstract

Elfamycins are a relatively understudied group of antibiotics that target the essential process of translation through impairment of EF-Tu function. For the most part, the utility of these compounds has been as laboratory tools for the study of EF-Tu and the ribosome, as their poor pharmacokinetic profile and solubility has prevented implementation as therapeutic agents. However, due to the slowing of the antibiotic pipeline and the rapid emergence of resistance to approved antibiotics, this group is being reconsidered. Some researchers are using screens for novel naturally produced variants, while others are making directed, systematic chemical improvements on publically disclosed compounds. As an example of the latter approach, a GE2270 A derivative, LFF571, has completed phase 2 clinical trials, thus demonstrating the potential for elfamycins to become more prominent antibiotics in the future.

Figure 1. Crystal Structures and Chemical Structures of EF-Tu and its inhibitors

(A) Crystal structures of the EF-Tu cycle. EF-Tu from Thermus aquaticus is indicated in purple, while bound GDP, GTP analogue, and/or magnesium ion are indicated in green. Top right: Crystal structure of active EF-Tu bound to GppNHp, a non-hydrolyzable GTP analogue (PDB ID: 1EXM). Bottom: Crystal structure of active EF-Tu bound to GppNHp and Phe-tRNA^Phe. Bound Phe-tRNAPhe is indicated in tan (PDB ID: 1TTT). Top left: After accommodation of the tRNA into the ribosomal A site, GTP is hydrolyzed to GDP. Structure of inactive EF-Tu bound to GDP (PDB ID: 1TUI). P-loop indicated in orange, Switch I in yellow, and Switch II in blue. Images drawn using Chimera (UCSF Chimera--a visualization system for exploratory research and analysis. Pettersen EF). (B) Chemical structures of EF-Tu inhibitors, drawn using ChemSketch (ACD/Chemsketch). (C) Crystal structures of inhibitors bound to EF-Tu. First: Kirromycin binds between domain 1 and 3 in the crystal structure of the EF-Tu:GppNHp:Phe-tRNA^Phe complex. Escherichia coli EF-Tu activated with a non-hydrolyzable GTP analogue, GppHNp, bound to Phe-tRNA^Phe and kirromycin. In the model, EF-Tu is indicated in purple, GppNHp in green, Phe-tRNA^Phe in tan, and kirromycin in cyan (PDB ID: 1OB2). Second: Enacyloxin IIa binds between domain 1 and 3 in the crystal structure of the EF-Tu:GppNHp:Phe-tRNA^Phe complex. T. aquaticus EF-Tu activated with a non-hydrolyzable GTP analogue, GppHNp, bound to Phe-tRNA^Phe and enacyloxin IIa. In the model, EF-Tu is indicated in purple, GppNHp in green, Phe-tRNA^Phe in tan, and enacyloxin IIa in magenta (PDB ID: 1OB5). Third: Pulvomycin binds at the interface of EF-Tu’s three domains in the crystal structure of EF-Tu:GppNHp complex. T. thermophilus EF-Tu activated with a non-hydrolyzable GTP analogue, GppHNp, bound to pulvomycin. In the model, EF-Tu is indicated in purple, GppNHp in green, and pulvomycin in orange (PDB ID: 2C78). Fourth: GE2270 A binds between domains 1 and 2 in the crystal structure of EF-Tu:GppNHp complex. T. thermophilus EF-Tu activated with a non-hydrolyzable GTP analogue, GppHNp, bound to GE2270 A. In the model, EF-Tu is indicated in purple, GppNHp in green, and GE2270 A in yellow (PDB ID: 2C77). Images drawn using Chimera (UCSF Chimera--a visualization system for exploratory research and analysis. Pettersen EF).