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.”

Ribosome biogenesis in disease: new players and therapeutic targets

“…115,137 Ribosome protection proteins such as the ATP-binding cassette subfamily F(ATP-F) are responsible for the resistance to a wide array of antibiotics. 305 Further research on the mechanisms underlying ATP-F-mediated ribosome protection will improve our understanding of antibiotic resistance and develop more efficient therapy.…”

A greater effect on clarithromycin resistance of mef(A)‐associated msr(D) than mef(E)‐associated msr(D) in Streptococcus pyogenes

“…Regarding the mechanism of msr (D)‐dependent macrolide resistance, there are two hypotheses: (i) Mef(A) is coupled to the cognate ATP‐binding protein Msr(D) to function as an efflux system 13 ; (ii) antibiotic‐resistance ABC‐F proteins, including Msr(D), rescue the translation from antibiotic‐mediated inhibition by driving the dissociation of bound antibiotic molecules from the ribosome 14 . Although we do not judge which of the two hypotheses is correct, more studies support the latter one 15–18 . The antibiotic‐resistance ABC‐F proteins are soluble, and have two nucleotide‐binding domains (Pfam accession number PF00005) separated by a flexible linker of approximately 80 amino acid residues 19 .…”

“…14 Although we do not judge which of the two hypotheses is correct, more studies support the latter one. [15][16][17][18] The antibiotic-resistance ABC-F proteins are soluble, and have two nucleotide-binding domains (Pfam accession number PF00005) separated by a flexible linker of approximately 80 amino acid residues. 19 The flexible linker is called Q-linker in the Msr(D) protein as described above (Figure 1).…”

Antibiotic resistance mechanism and diagnosis of common foodborne pathogens based on genotypic and phenotypic biomarkers

“…Generally, the mechanism of target protection requires sustained or repeated direct interactions between the resistant protein and the target to develop antibiotic resistance, and no permanent changes are caused to the properties of the target. Common resistant proteins include tetracycline ribosomal protective protein (TRPPs; e.g., TetM, TetO), quinolone resistance protein (e.g., Qnr), antibiotic resistance (ARE) ABC‐F protein (e.g., Msr, Vga, Lsa, Sal, Vml), FusB‐type proteins, and cis‐acting peptides (Eiamsam‐ang et al., 2022; Ero et al., 2021; Li et al., 2022; Slettemeås et al., 2019). TRPPs mediate the target protection against the tetracycline via the binding to the 30S ribosome subunit to obstruct the transmission of incoming aminoyl‐TrNA through the extension factor Tu (EF‐TU) during the extension phase of protein synthesis, which inhibits the bacterial translation (Ero et al., 2021; Founou et al., 2019).…”