title: A novel pleuromutilin antibacterial compound, its binding mode and selectivity mechanism.
abstract: The increasing appearance of pathogenic bacteria with antibiotic resistance is a global threat. Consequently, clinically available potent antibiotics that are active against multidrug resistant pathogens are becoming exceedingly scarce. Ribosomes are a main target for antibiotics, and hence are an objective for novel drug development. Lefamulin, a semi-synthetic pleuromutilin compound highly active against multi-resistant pathogens, is a promising antibiotic currently in phase III trials for the treatment of community-acquired bacterial pneumonia in adults. The crystal structure of the Staphylococcus aureus large ribosomal subunit in complex with lefamulin reveals its protein synthesis inhibition mechanism and the rationale for its potency. In addition, analysis of the bacterial and eukaryotes ribosome structures around the pleuromutilin binding pocket has elucidated the key for the drug's selectivity.
authors.affiliation: Department of Structural Biology, Weizmann Institute of Science, Rehovot 7610001, Israel.
authors.forename: Zohar
authors.initials: Z
authors.lastname: Eyal
authors.affiliation: Department of Structural Biology, Weizmann Institute of Science, Rehovot 7610001, Israel.
authors.forename: Donna
authors.initials: D
authors.lastname: Matzov
authors.affiliation: Department of Structural Biology, Weizmann Institute of Science, Rehovot 7610001, Israel.
authors.forename: Miri
authors.initials: M
authors.lastname: Krupkin
authors.affiliation: Nabriva Therapeutics AG, 1110 Vienna, Austria.
authors.forename: Susanne
authors.initials: S
authors.lastname: Paukner
authors.affiliation: Nabriva Therapeutics AG, 1110 Vienna, Austria.
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Riedl
authors.affiliation: Department of Structural Biology, Weizmann Institute of Science, Rehovot 7610001, Israel.
authors.forename: Haim
authors.initials: H
authors.lastname: Rozenberg
authors.affiliation: Department of Structural Biology, Weizmann Institute of Science, Rehovot 7610001, Israel.
authors.forename: Ella
authors.initials: E
authors.lastname: Zimmerman
authors.affiliation: Department of Structural Biology, Weizmann Institute of Science, Rehovot 7610001, Israel.
authors.forename: Anat
authors.initials: A
authors.lastname: Bashan
authors.affiliation: Department of Structural Biology, Weizmann Institute of Science, Rehovot 7610001, Israel.
authors.forename: Ada
authors.initials: A
authors.lastname: Yonath
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D001426:Bacterial Proteins / Q000096:biosynthesis; D017326:Clinical Trials, Phase III as Topic; D004224:Diterpenes / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D011083:Polycyclic Compounds; D014176:Protein Biosynthesis / Q000187:drug effects; D054681:Ribosome Subunits, Large, Bacterial / Q000737:chemistry / Q000378:metabolism; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D013211:Staphylococcus aureus / Q000737:chemistry / Q000254:growth & development; D000097567:Pleuromutilins
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D004224:Diterpenes; D011083:Polycyclic Compounds; D000097567:Pleuromutilins