ABC-F proteins in mRNA translation and antibiotic resistance

Ousalem, Farès; Singh, Samiksha; Chesneau, O.; Hunt, J.F.; Boël, Grégory

doi:10.1016/j.resmic.2019.09.005

Cited by 31 publications

(51 citation statements)

References 86 publications

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“…The linker connecting the two tandem ABC domains is a defining feature of the ABC-F family, and the loop region of the linker forms stereospecific contact near the PTC in the ribosome [20]. Unlike MsrE and VgaALC variants, truncation of the loop region completely abolished resistance to pleuromutilins, lincosamides, and streptogramin A [22,23].…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, Lys206Ala, Ser211Ala, Trp213Ala, Met218Ala, and Met219Ala substitutions reduced PLSA resistance to different degrees. This variation is presumably because mutations reduce the size of the sidechain that penetrates most deeply into the PTC in SrpA, thereby eliminating steric clashes with valnemulin and reducing the magnitude of the relatively small allosteric conformational changes in the PTC upon SrpA binding [20].…”

Section: Discussionmentioning

confidence: 99%

“…Hence, these strains were chosen for an in-depth analysis of the molecular basis of pleuromutilin resistance. A pan-genome analysis was used to compare gene distributions between tiamulin-susceptible and -resistant isolates, with a focus on ORFs annotated as ATP-binding proteins, which have been implicated in pleuromutilin resistance [20]. As depicted in heatmaps ( Fig.…”

Section: Identification and Characterization Of A Novel Pleuromutilinmentioning

confidence: 99%

“…The structure of SrpA was predicted to possess conserved features of antibiotic resistance ABC-F family proteins, such as two ABC transporter domains (ABC1 and ABC2) carrying highly conserved nucleotide-binding sites (NBSs) (residues 36-43 and 303-310) assembled at its base, and a domain linker (residues 163-250) that forms two long crossed helices (α1 and α2) connected by an extended loop (residues 203-224) (Fig. 3A) [20,25].…”

Section: Homology Modeling and Molecular Docking Of Srpamentioning

confidence: 99%

“…Resistance to pleuromutilins is commonly attributed to the acquisition of endogenous mutations in 23S rRNA or horizontally transmitted resistance determinants, such as the rRNA methyltransferase Cfr or the antibiotic resistance ATP-binding cassette (ABC) F family proteins-Vga/Lsa/Sal/VmlR [4,7,19]. Antibiotic resistance ABC-F family genes have been found in the genomes of numerous pathogens and confer resistance to a broad range of clinically relevant antibiotics targeting the ribosomes [20][21][22]. Unlike other ABC superfamily members that actively pump drugs out of the membranes, the ABC-F family proteins do not fuse to transmembrane domains (TMDs).…”

Section: Introductionmentioning

confidence: 99%

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Characterization of a novel gene,srpA, conferring resistance to streptogramin A, pleuromutilins, and lincosamides inStreptococcus suis

Zhang¹,

Liu²,

Zhang³

et al. 2020

Preprint

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Antimicrobial resistance is undoubtedly one of the greatest global health threats. The emergence of multidrug resistant (MDR) gram positive pathogens, like methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecium, and β-lactamase resistant Streptococcus pneumonia, has severely limited our antibiotic arsenal. Numerous ribosome-targeting antibiotics, especially pleuromutilins, oxazolidinones, and streptogramins, are viewed as promising alternatives against aggressive MDR pathogens. In this study, we identified a new ABC F family determinant, srpA, in Streptococcus suis by a comparative analysis of whole genome sequences of tiamulin resistant and sensitive bacteria. Functional cloning confirmed that the deduced gene can mediate cross-resistance to pleuromutilins, lincosamides, and streptogramin A in S. suis and S. aureus. A sequence alignment revealed that srpA shares the highest amino acid identity with Vga(E) (36%) and shows canonical characteristics of ABC F family members. In SrpA ribosome docked compounds, the extended loop region of SrpA approaches the valnemulin binding pocket in the ribosome peptidyl transferase center and competes with bound valnemulin. A detailed mutational analysis of the loop residues confirmed that this domain is crucial for SrpA activity, as substitutions or truncations of this region affect the efficiency and specificity of antibiotic resistance. A ribosome binding assay supported the protective effects of SrpA on the ribosome by preventing antibiotic binding as well as displacing bound drugs. These findings clarify the mechanisms underlying resistance to ribosomal antibiotics.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Identification and Characterization Of A Novel Pleuromutilinmentioning

confidence: 99%

Section: Homology Modeling and Molecular Docking Of Srpamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Characterization of a novel gene,srpA, conferring resistance to streptogramin A, pleuromutilins, and lincosamides inStreptococcus suis

Zhang¹,

Liu²,

Zhang³

et al. 2020

Preprint

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ABC‐F translation factors: from antibiotic resistance to immune response

et al. 2020

Self Cite

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Energy-dependent Translational Throttle A (EttA) from E. coli is a paradigmatic ABC-F protein that controls the first step in polypeptide elongation on the ribosome according to the cellular energy status. Biochemical and structural studies have established that ABC-F proteins generally function as translation factors that modulate the conformation of the peptidyl transferase center upon binding to the ribosomal tRNA exit site. These factors, present in both prokaryotes and eukaryotes but not in archaea, use related molecular mechanisms to modulate protein synthesis for heterogenous purposes, ranging from antibiotic resistance and rescue of stalled ribosomes to modulation of the mammalian immune response. Here we review the canonical studies characterizing the phylogeny, regulation, ribosome interactions, and mechanisms of action of the bacterial ABC-F proteins, and discuss the implications of these studies for the molecular function of eukaryotic ABC-F proteins, including the three human family members.

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Evolutionary history of ATP‐binding cassette proteins

Srikant

2020

FEBS Letters

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ATP‐binding cassette (ABC) proteins are found in every sequenced genome and evolved deep in the phylogenetic tree of life. ABC proteins form one of the largest homologous protein families, with most being involved in substrate transport across biological membranes, and a few cytoplasmic members regulating in essential processes like translation. The predominant ABC protein classification scheme is derived from human members, but the increasing number of fully sequenced genomes permits to reevaluate this paradigm in the light of the evolutionary history the ABC‐protein superfamily. As we study the diversity of substrates, mechanisms, and physiological roles of ABC proteins, knowledge of the evolutionary relationships highlights similarities and differences that can be attributed to specific branches in protein divergence. While alignments and trees built on natural sequence variation account for the evolutionary divergence of ABC proteins, high‐throughput experiments and next‐generation sequencing creating experimental sequence variation are instrumental in identifying functional constraints. The combination of natural and experimentally produced sequence variation allows a broader and more rational study of the function and physiological roles of ABC proteins.

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ABC-F proteins in mRNA translation and antibiotic resistance

Cited by 31 publications

References 86 publications

Characterization of a novel gene,srpA, conferring resistance to streptogramin A, pleuromutilins, and lincosamides inStreptococcus suis

Characterization of a novel gene,srpA, conferring resistance to streptogramin A, pleuromutilins, and lincosamides inStreptococcus suis

ABC‐F translation factors: from antibiotic resistance to immune response

Evolutionary history of ATP‐binding cassette proteins

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