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

Research output: Contribution to journalArticle

Abstract

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.

Details

Authors
  • 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
Organisations
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
Volume12
Issue number1
Publication statusPublished - 2021 Dec
Publication categoryResearch
Peer-reviewedYes