Targeting Multiple Aminoacyl-tRNA Synthetases Overcomes the Resistance Liabilities Associated with Antibacterial Inhibitors Acting on a Single Such Enzyme

• Published in: Antimicrobial agents and chemotherapy Vol. 60; no. 10; pp. 6359 - 6361
• Main Authors: Randall, Christopher P., Rasina, Dace, Jirgensons, Aigars, O'Neill, Alex J.
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 01.10.2016
• Subjects: Amino Acyl-tRNA Synthetases; Amino Acyl-tRNA Synthetases - antagonists & inhibitors; Anti-Bacterial Agents; Anti-Bacterial Agents - pharmacology; Boron Compounds - pharmacology; Diamines - pharmacology; Drug Resistance, Bacterial; Drug Resistance, Bacterial - drug effects; Enzyme Inhibitors; Enzyme Inhibitors - pharmacology; Mechanisms of Resistance; Microbial Sensitivity Tests; Molecular Targeted Therapy; Mupirocin - pharmacology; Mutation Rate; Staphylococcus aureus; Staphylococcus aureus - drug effects; Staphylococcus aureus - genetics; Thiophenes - pharmacology
• ISSN: 0066-4804; 1098-6596; 1098-6596
• DOI: 10.1128/AAC.00674-16

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.