Ribosome Protection Proteins-"New" Players in the Global Arms Race with Antibiotic-Resistant Pathogens

Abstract

Bacteria have evolved an array of mechanisms enabling them to resist the inhibitory effect of antibiotics, a significant proportion of which target the ribosome. Indeed, resistance mechanisms have been identified for nearly every antibiotic that is currently used in clinical practice. With the ever-increasing list of multi-drug-resistant pathogens and very few novel antibiotics in the pharmaceutical pipeline, treatable infections are likely to become life-threatening once again. Most of the prevalent resistance mechanisms are well understood and their clinical significance is recognized. In contrast, ribosome protection protein-mediated resistance has flown under the radar for a long time and has been considered a minor factor in the clinical setting. Not until the recent discovery of the ATP-binding cassette family F protein-mediated resistance in an extensive list of human pathogens has the significance of ribosome protection proteins been truly appreciated. Understanding the underlying resistance mechanism has the potential to guide the development of novel therapeutic approaches to evade or overcome the resistance. In this review, we discuss the latest developments regarding ribosome protection proteins focusing on the current antimicrobial arsenal and pharmaceutical pipeline as well as potential implications for the future of fighting bacterial infections in the time of "superbugs."

Keywords: ABC-F proteins; antibiotic resistance; novel antibiotics; ribosome protection.

Figure 1

Three models of ribosome protection protein-mediated antibiotic resistance. (A) A model for ribosome protection against tetracycline (TET) mediated by the TetM protein. Drug-stalled ribosome with tRNA in the P-site (green) is rescued by TetM (pink), which competes with TET (shown with star) in the A-site, thereby purging it from the ribosome. The subsequent GTP hydrolysis-dependent release of TetM from the ribosome enables protein synthesis to resume. (B) A model for ribosome protection against fusidic acid (FA) mediated by the FusB protein. FA interaction with elongation factor G (EF-G) prevents its dissociation from the ribosome. FusB (lime green) interacts with the ribosome-bound EF-G, leading to its release and allowing translation to proceed in the presence of FA. The domains G, G’, II, III, IV, and V of EF-G are colored green, blue, deep salmon, yellow, and sky blue, respectively. An enlarged view of the FA binding pocket is shown, involving EF-G domains G, II, and III. EF-G switch II (residues 82–102) is colored red and the 23S ribosomal RNA sarcin-ricin loop (SRL) is colored gray. In addition, GDP and Mg²⁺ in the vicinity of FA are also shown. Notably, FusB does not interact with the same region of EF-G as FA and there is no evidence for direct physical displacement of the drug. (C) A model for ribosomes protection against various classes of PTC/NPET-targeting AB mediated by the ARE ABC-F proteins. Two representatives of ARE ABC-F proteins, MsrE (yellow) and VmlR (dark green), are shown to bind to the E-site of the drug-stalled ribosome. Their antibiotic resistance domain (ARD) distorts the tRNA in the P-site (green) in order to access the drug-binding site. Allosteric and/or steric interactions in PTC promote the dissociation of drugs. ATP binding may promote RPP–ribosome interaction, while ATP hydrolysis leads to the dissociation of RPP from the ribosome. Drugs corresponding to MsrE and VmlR are azithromycin and lincomycin, respectively (also shown with stars). Ribosomes with gray and orange large subunits represent translationally inactive and active complexes, respectively.