Structural basis of ABCF-mediated resistance to pleuromutilin, lincosamide, and streptogramin A antibiotics in Gram-positive pathogens

Research output: Contribution to journalArticle


Target protection proteins confer resistance to the host organism by directly binding to the antibiotic target. One class of such proteins are the antibiotic resistance (ARE) ATP-binding cassette (ABC) proteins of the F-subtype (ARE-ABCFs), which are widely distributed throughout Gram-positive bacteria and bind the ribosome to alleviate translational inhibition from antibiotics that target the large ribosomal subunit. Here, we present single-particle cryo-EM structures of ARE-ABCF-ribosome complexes from three Gram-positive pathogens: Enterococcus faecalis LsaA, Staphylococcus haemolyticus VgaALC and Listeria monocytogenes VgaL. Supported by extensive mutagenesis analysis, these structures enable a general model for antibiotic resistance mediated by these ARE-ABCFs to be proposed. In this model, ABCF binding to the antibiotic-stalled ribosome mediates antibiotic release via mechanistically diverse long-range conformational relays that converge on a few conserved ribosomal RNA nucleotides located at the peptidyltransferase center. These insights are important for the future development of antibiotics that overcome such target protection resistance mechanisms.


  • Caillan Crowe-McAuliffe
  • Victoriia Murina
  • Kathryn Jane Turnbull
  • Marje Kasari
  • Merianne Mohamad
  • Christine Polte
  • Hiraku Takada
  • Karolis Vaitkevicius
  • Jörgen Johansson
  • Zoya Ignatova
  • Gemma C. Atkinson
  • Alex J. O’Neill
  • Vasili Hauryliuk
  • Daniel N. Wilson
External organisations
  • University of Hamburg
  • Umeå University
  • University of Leeds
  • University of Tartu
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Biochemistry and Molecular Biology
  • Microbiology in the medical area
Original languageEnglish
Article number3577
JournalNature Communications
Issue number1
Publication statusPublished - 2021 Dec
Publication categoryResearch