Structural basis of ABCF-mediated resistance to pleuromutilin, lincosamide, and streptogramin A antibiotics in Gram-positive pathogens
| Autor: | Marje Kasari, Christine Polte, Hiraku Takada, Zoya Ignatova, Kathryn Jane Turnbull, Gemma C. Atkinson, Merianne Mohamad, Victoriia Murina, Daniel N. Wilson, Alex J. O'Neill, Vasili Hauryliuk, Jörgen Johansson, Caillan Crowe-McAuliffe, Karolis Vaitkevicius |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Models
Molecular 0301 basic medicine Streptogramins Protein Conformation medicine.drug_class Science 030106 microbiology Antibiotics General Physics and Astronomy Drug resistance Biology Antimicrobial resistance Gram-Positive Bacteria Article General Biochemistry Genetics and Molecular Biology Bacterial genetics Microbiology 03 medical and health sciences chemistry.chemical_compound Antibiotic resistance Protein structure Bacterial Proteins Drug Resistance Bacterial medicine Polycyclic Compounds RNA Messenger Adhesins Bacterial Lincosamides Streptogramin A Binding Sites Multidisciplinary Cryoelectron Microscopy Biochemistry and Molecular Biology General Chemistry Ribosome Anti-Bacterial Agents Bacterial adhesin 030104 developmental biology chemistry Peptidyl Transferases RNA ATP-Binding Cassette Transporters Diterpenes Ribosomes Pleuromutilin Biokemi och molekylärbiologi |
| Zdroj: | Nature Communications Nature Communications, Vol 12, Iss 1, Pp 1-14 (2021) |
| ISSN: | 2041-1723 |
| Popis: | 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. 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. |
| Databáze: | OpenAIRE |
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