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

Crowe-McAuliffe C, Murina V, Turnbull KJ, Kasari M, Mohamad M, Polte C, Takada H, Vaitkevicius K, Johansson J, Ignatova Z, Atkinson GC, O'Neill AJ, Hauryliuk V, Wilson DN

Nat Commun 12 (1) 3577 [2021-06-11; online 2021-06-11]

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.

Cryo-EM [Service]

PubMed 34117249

DOI 10.1038/s41467-021-23753-1

Crossref 10.1038/s41467-021-23753-1

pii: 10.1038/s41467-021-23753-1
pmc: PMC8196190

Publications 7.1.2