title: Evaluation of the characteristics of leucyl-tRNA synthetase (LeuRS) inhibitor AN3365 in combination with different antibiotic classes.
abstract: Aminoacyl tRNA synthetases are enzymes involved in the key process of coupling an amino acid to its cognate tRNA. AN3365 is a novel antibiotic that specifically targets leucyl-tRNA synthetase, whose development was halted after evaluation in phase II clinical trials owing to the rapid selection of resistance. In an attempt to bring AN3365 back into the developmental pipeline we have evaluated the efficacy of AN3365 in combination with different classes of antibiotic and characterized its mechanism of action. Although we detect no synergy or antagonism in combination with a range of antibiotic classes, a combination of AN3365 with colistin reduces the accumulation of AN3365-resistant and colistin resistance mutations. We also demonstrate that treatment with AN3365 results in the dramatic accumulation of the alarmone (p)ppGpp, the effector of the stringent response-a key player in antibiotic tolerance.
authors: Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center Rotterdam (Erasmus MC), Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands.
authors: C G
authors: CG
authors: Monteferrante
authors: Latvian Institute of Organic Synthesis, Riga, Latvia.
authors: A
authors: A
authors: Jirgensons
authors: Institute of Technology, University of Tartu, Nooruse 1, 50411, Tartu, Estonia.|Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University, Building 6K and 6L, University Hospital Area, 901 87, Umeå, Sweden.
authors: V
authors: V
authors: Varik
authors: Institute of Technology, University of Tartu, Nooruse 1, 50411, Tartu, Estonia.|Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University, Building 6K and 6L, University Hospital Area, 901 87, Umeå, Sweden.
authors: V
authors: V
authors: Hauryliuk
authors: Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center Rotterdam (Erasmus MC), Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands.
authors: W H F
authors: WH
authors: Goessens
authors: Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center Rotterdam (Erasmus MC), Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands. j.hays@erasmusmc.nl.
authors: J P
authors: JP
authors: Hays
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D004347:Drug Interactions; D024881:Drug Resistance, Bacterial; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006090:Gram-Negative Bacteria / Q000187:drug effects* / Q000201:enzymology; D006094:Gram-Positive Bacteria / Q000187:drug effects* / Q000201:enzymology; D007935:Leucine-tRNA Ligase / Q000037:antagonists & inhibitors*; D009154:Mutation
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D007935:Leucine-tRNA Ligase