Mechanism of tetracycline resistance by ribosomal protection protein Tet(O)

Abstract

Tetracycline resistance protein Tet(O), which protects the bacterial ribosome from binding the antibiotic tetracycline, is a translational GTPase with significant similarity in both sequence and structure to the elongation factor EF-G. Here, we present an atomic model of the Tet(O)-bound 70S ribosome based on our cryo-electron microscopic reconstruction at 9.6 Å resolution. This atomic model allowed us to identify the Tet(O)-ribosome binding sites, which involve three characteristic loops in domain 4 of Tet(O). Replacements of the three-amino acid tips of these loops by a single glycine residue result in loss of Tet(O)-mediated tetracycline resistance. On the basis of these findings, the mechanism of Tet(O)-mediated tetracycline resistance can be explained in molecular detail.

Conserved GTPase LepA (Elongation Factor 4) functions in biogenesis of the 30S subunit of the 70S ribosome

“…Structures of various trGTPases (including EF-G, RF3, TetM, BipA, and LepA) bound to the ribosome provide evidence that these factors all bind similarly, with domains G and II contacting the LSU and SSU, respectively (25)(26)(27)(28)(29). The GTPase activity of trGTPases, including LepA (19), is most greatly stimulated by 70S ribosomes.…”

Disease Manifestations and Pathogenic Mechanisms of Group A Streptococcus

“…These proteins share homology with elongation factors EF-G and EF-Tu and possess GTPase activity that is important for the displacement of tetracycline from the ribosome (510,511). Efflux pumps for tetracycline encoded by the tet(K) or tet(L) gene also confer tetracycline resistance; however, in contrast to macrolide resistance, these efflux pumps are relatively uncommon in streptococci (512,513).…”

A Bright Future for Antibiotics?

“…Prominent processes acquiring resistance include modifications of the antibiotic binding pockets by mutations (e.g., macrolide resistance by modification of a component crucial for their binding, A2058G). Other frequently used mechanisms include activation of key enzymatic processes (e.g., methylation of the binding components of macrolide and aminoglycosides by methylases); enzymatic inactivation of the drug, such as the macrolide molecule by esterases (61); removal of the antibiotic drug from its target (i.e., resistance to tetracycline by disturbing the ribosomal protection proteins) (62)(63)(64)(65); and modification of ribosomal proteins essential for ribosomal functionality at the PTC and tunnel entrance, such as rpL3, which is associated with resistance to linezolid, tiamulin, and anisomycin (66,67), or disruption of the interactions between proteins that play key roles in protein biosynthesis (68).…”