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Structure and function of FusB: an elongation factor G-binding fusidic acid resistance protein active in ribosomal translocation and recycling.

Guo X, Peisker K, Bäckbro K, Chen Y, Koripella RK, Mandava CS, Sanyal S, Selmer M
Open Biol 2 120016 (2012)
Cited: 19 times
EuropePMC logo PMID: 22645663

Abstract

Fusidic acid (FA) is a bacteriostatic antibiotic that locks elongation factor G (EF-G) to the ribosome after GTP hydrolysis during elongation and ribosome recycling. The plasmid pUB101-encoded protein FusB causes FA resistance in clinical isolates of Staphylococcus aureus through an interaction with EF-G. Here, we report 1.6 and 2.3 Å crystal structures of FusB. We show that FusB is a two-domain protein lacking homology to known structures, where the N-terminal domain is a four-helix bundle and the C-terminal domain has an alpha/beta fold containing a C4 treble clef zinc finger motif and two loop regions with conserved basic residues. Using hybrid constructs between S. aureus EF-G that binds to FusB and Escherichia coli EF-G that does not, we show that the sequence determinants for FusB recognition reside in domain IV and involve the C-terminal helix of S. aureus EF-G. Further, using kinetic assays in a reconstituted translation system, we demonstrate that FusB can rescue FA inhibition of tRNA translocation as well as ribosome recycling. We propose that FusB rescues S. aureus from FA inhibition by preventing formation or facilitating dissociation of the FA-locked EF-G-ribosome complex.

Articles - 4ado mentioned but not cited (1)

  1. Structure and function of FusB: an elongation factor G-binding fusidic acid resistance protein active in ribosomal translocation and recycling. Guo X, Peisker K, Bäckbro K, Chen Y, Koripella RK, Mandava CS, Sanyal S, Selmer M. Open Biol 2 120016 (2012)


Reviews citing this publication (5)

  1. Ribosome-targeting antibiotics and mechanisms of bacterial resistance. Wilson DN. Nat Rev Microbiol 12 35-48 (2014)
  2. The bacterial translation stress response. Starosta AL, Lassak J, Jung K, Wilson DN. FEMS Microbiol Rev 38 1172-1201 (2014)
  3. Target protection as a key antibiotic resistance mechanism. Wilson DN, Hauryliuk V, Atkinson GC, O'Neill AJ. Nat Rev Microbiol 18 637-648 (2020)
  4. Fusidic Acid: A Bacterial Elongation Factor Inhibitor for the Oral Treatment of Acute and Chronic Staphylococcal Infections. Fernandes P. Cold Spring Harb Perspect Med 6 a025437 (2016)
  5. Ribosome Protection Proteins-"New" Players in the Global Arms Race with Antibiotic-Resistant Pathogens. Ero R, Yan XF, Gao YG. Int J Mol Sci 22 5356 (2021)

Articles citing this publication (13)

  1. Mechanism of elongation factor-G-mediated fusidic acid resistance and fitness compensation in Staphylococcus aureus. Koripella RK, Chen Y, Peisker K, Koh CS, Selmer M, Sanyal S. J Biol Chem 287 30257-30267 (2012)
  2. Skin Commensal Staphylococci May Act as Reservoir for Fusidic Acid Resistance Genes. Hung WC, Chen HJ, Lin YT, Tsai JC, Chen CW, Lu HH, Tseng SP, Jheng YY, Leong KH, Teng LJ. PLoS One 10 e0143106 (2015)
  3. A novel fusidic acid resistance determinant, fusF, in Staphylococcus cohnii. Chen HJ, Hung WC, Lin YT, Tsai JC, Chiu HC, Hsueh PR, Teng LJ. J Antimicrob Chemother 70 416-419 (2015)
  4. Distribution of antibiotic resistance genes among Staphylococcus species isolated from ready-to-eat foods. Wang YT, Lin YT, Wan TW, Wang DY, Lin HY, Lin CY, Chen YC, Teng LJ. J Food Drug Anal 27 841-848 (2019)
  5. A target-protection mechanism of antibiotic resistance at atomic resolution: insights into FusB-type fusidic acid resistance. Tomlinson JH, Thompson GS, Kalverda AP, Zhuravleva A, O'Neill AJ. Sci Rep 6 19524 (2016)
  6. Fusidic acid resistance in Staphylococcus aureus nasal carriage strains in nine European countries. den Heijer CD, van Bijnen EM, Paget WJ, Stobberingh EE. Future Microbiol 9 737-745 (2014)
  7. New insights into the enzymatic role of EF-G in ribosome recycling. Zhang D, Yan K, Zhang Y, Liu G, Cao X, Song G, Xie Q, Gao N, Qin Y. Nucleic Acids Res 43 10525-10533 (2015)
  8. Mechanism of fusidic acid inhibition of RRF- and EF-G-dependent splitting of the bacterial post-termination ribosome. Borg A, Pavlov M, Ehrenberg M. Nucleic Acids Res 44 3264-3275 (2016)
  9. Mutagenesis mapping of the protein-protein interaction underlying FusB-type fusidic acid resistance. Cox G, Edwards TA, O'Neill AJ. Antimicrob Agents Chemother 57 4640-4644 (2013)
  10. Transcriptomic and Metabolomic Analysis of a Fusidic Acid-Selected fusA Mutant of Staphylococcus aureus. Gupta SK, Pfeltz RF, Wilkinson BJ, Gustafson JE. Antibiotics (Basel) 11 1051 (2022)
  11. Biochemical and Cellular Characterization of the Function of Fluorophosphonate-Binding Hydrolase H (FphH) in Staphylococcus aureus Support a Role in Bacterial Stress Response. Fellner M, Walsh A, Dela Ahator S, Aftab N, Sutherland B, Tan EW, Bakker AT, Martin NI, van der Stelt M, Lentz CS. ACS Infect Dis 9 2119-2132 (2023)
  12. Staphylococcus aureus-Cure-Associated Antigens Elicit Type 3 Immune Memory T Cells. Santos KR, Souza FN, Ramos-Sanchez EM, Batista CF, Reis LC, Fotoran WL, Heinemann MB, Cunha AF, Rocha MC, Faria AR, Andrade HM, Cerqueira MMOP, Gidlund M, Goto H, Della Libera AMMP. Antibiotics (Basel) 11 1831 (2022)
  13. Enterococcus faecalis OG1RF Evolution at Low pH Selects Fusidate-Sensitive Mutants in Elongation Factor G and at High pH Selects Defects in Phosphate Transport. Fitzgerald BA, Wadud A, Slimak Z, Slonczewski JL. Appl Environ Microbiol 89 e0046623 (2023)


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