title: Targeting Multiple Aminoacyl-tRNA Synthetases Overcomes the Resistance Liabilities Associated with Antibacterial Inhibitors Acting on a Single Such Enzyme.
abstract: Bacterial aminoacyl-tRNA synthetases (aaRSs) represent promising antibacterial drug targets. Unfortunately, the aaRS inhibitors that have to date reached clinical trials are subject to rapid resistance development through mutation, a phenomenon that limits their potential clinical utility. Here, we confirm the intuitively correct idea that simultaneous targeting of two different aaRS enzymes prevents the emergence of spontaneous bacterial resistance at high frequency, a finding that supports the development of multitargeted anti-aaRS therapies.
authors.affiliation: Antimicrobial Research Centre and School of Molecular and Cellular Biology, University of Leeds, Leeds, United Kingdom.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Randall
authors.affiliation: Latvian Institute of Organic Synthesis, Riga, Latvia.
authors.forename: Dace
authors.initials: D
authors.lastname: Rasina
authors.affiliation: Latvian Institute of Organic Synthesis, Riga, Latvia.
authors.forename: Aigars
authors.initials: A
authors.lastname: Jirgensons
authors.affiliation: Antimicrobial Research Centre and School of Molecular and Cellular Biology, University of Leeds, Leeds, United Kingdom a.j.oneill@leeds.ac.uk.
authors.forename: Alex J
authors.initials: AJ
authors.lastname: O'Neill
mesh_terms: D000604:Amino Acyl-tRNA Synthetases / Q000037:antagonists & inhibitors*; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001896:Boron Compounds / Q000494:pharmacology; D003959:Diamines / Q000494:pharmacology; D024881:Drug Resistance, Bacterial / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D058990:Molecular Targeted Therapy; D016712:Mupirocin / Q000494:pharmacology; D059645:Mutation Rate; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics; D013876:Thiophenes / Q000494:pharmacology
chemical_list: C583949:3-(aminomethyl)-7-(3-hydroxypropoxy)-1-hydroxy-1,3-dihydro-2,1-benzoxaborole; D000900:Anti-Bacterial Agents; D001896:Boron Compounds; D003959:Diamines; D004791:Enzyme Inhibitors; C533960:REP8839; D013876:Thiophenes; D016712:Mupirocin; D000604:Amino Acyl-tRNA Synthetases