Journal Article

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

Atkinson, Gemma C., Kasari, Marje, Takada, Hiraku, Vaitkevicius, Karolis, Wilson, Daniel N., O’Neill, Alex J., Polte, Christine, Johansson, Jörgen, Mohamad, Merianne, Turnbull, Kathryn Jane, Ignatova, Zoya, Murina, Victoriia, Crowe-McAuliffe, Caillan, Hauryliuk, Vasili

2021

Overview

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 VgaA LC 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. Mitochondrial ribosomes (mitoribosomes) are characterized by a distinct architecture and thus biogenesis pathway. Here, cryo-EM structures of mitoribosome large subunit assembly intermediates elucidate final steps of 16 S rRNA folding, methylation and peptidyl transferase centre (PTC) completion, as well as functions of several mitoribosome assembly factors.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 101/28 / 38/61 / 631/326/22/1434 / 631/337/574/1789 / 631/45/500 / 631/535/1258/1259 / 82/1 / 82/29 / 82/80 / 82/83 / Adenosine triphosphate / Adhesins, Bacterial - chemistry / Adhesins, Bacterial - genetics / Anti-Bacterial Agents - pharmacology / Antibiotic resistance / Antibiotics / Assembly / ATP-Binding Cassette Transporters - chemistry / ATP-Binding Cassette Transporters - genetics / ATP-Binding Cassette Transporters - metabolism / Bacteria / Bacterial Proteins - chemistry / Bacterial Proteins - genetics / Bacterial Proteins - metabolism / Basic Medicine / Binding / Binding Sites / Biologi / Biological Sciences / Cryoelectron Microscopy / Diterpenes - pharmacology / Drug resistance / Drug Resistance, Bacterial - drug effects / Drug Resistance, Bacterial - genetics / Enterococcus faecalis / Gram-positive bacteria / Gram-Positive Bacteria - drug effects / Gram-Positive Bacteria - genetics / Humanities and Social Sciences / Intermediates / Lincosamides - pharmacology / Listeria / Listeria monocytogenes / Medical and Health Sciences / Medicin och hälsovetenskap / Medicinska och farmaceutiska grundvetenskaper / Microbiology in the Medical Area / Mikrobiologi inom det medicinska området / Mitochondria / Models, Molecular / multidisciplinary / Mutagenesis / Natural Sciences / Naturvetenskap / Nucleotides / Pathogens / Peptidyl Transferases - metabolism / Peptidyltransferase / Pleuromutilins / Polycyclic Compounds - pharmacology / Protein Conformation / Proteins / Ribosomes / Ribosomes - metabolism / RNA, Messenger / rRNA / Science / Science (multidisciplinary) / Staphylococcus haemolyticus / Streptogramins - pharmacology