Development of Methionyl-tRNA Synthetase Inhibitors as Antibiotics for Gram-Positive Bacterial Infections.

Autor:	Faghih O; Department of Medicine, University of Washington, Seattle, Washington, USA., Zhang Z; Department of Biochemistry, University of Washington, Seattle, Washington, USA., Ranade RM; Department of Medicine, University of Washington, Seattle, Washington, USA., Gillespie JR; Department of Medicine, University of Washington, Seattle, Washington, USA., Creason SA; Department of Medicine, University of Washington, Seattle, Washington, USA., Huang W; Department of Biochemistry, University of Washington, Seattle, Washington, USA., Shibata S; Department of Biochemistry, University of Washington, Seattle, Washington, USA., Barros-Álvarez X; Department of Biochemistry, University of Washington, Seattle, Washington, USA.; Laboratorio de Enzimología de Parásitos, Facultad de Ciencias, Universidad de los Andes, Mérida, Venezuela., Verlinde CLMJ; Department of Biochemistry, University of Washington, Seattle, Washington, USA., Hol WGJ; Department of Biochemistry, University of Washington, Seattle, Washington, USA., Fan E; Department of Biochemistry, University of Washington, Seattle, Washington, USA., Buckner FS; Department of Medicine, University of Washington, Seattle, Washington, USA fbuckner@uw.edu.
Jazyk:	angličtina
Zdroj:	Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2017 Oct 24; Vol. 61 (11). Date of Electronic Publication: 2017 Oct 24 (Print Publication: 2017).
DOI:	10.1128/AAC.00999-17
Abstrakt:	Antibiotic-resistant bacteria are widespread and pose a growing threat to human health. New antibiotics acting by novel mechanisms of action are needed to address this challenge. The bacterial methionyl-tRNA synthetase (MetRS) enzyme is essential for protein synthesis, and the type found in Gram-positive bacteria is substantially different from its counterpart found in the mammalian cytoplasm. Both previously published and new selective inhibitors were shown to be highly active against Gram-positive bacteria with MICs of ≤1.3 μg/ml against Staphylococcus , Enterococcus , and Streptococcus strains. Incorporation of radioactive precursors demonstrated that the mechanism of activity was due to the inhibition of protein synthesis. Little activity against Gram-negative bacteria was observed, consistent with the fact that Gram-negative bacterial species contain a different type of MetRS enzyme. The ratio of the MIC to the minimum bactericidal concentration (MBC) was consistent with a bacteriostatic mechanism. The level of protein binding of the compounds was high (>95%), and this translated to a substantial increase in MICs when the compounds were tested in the presence of serum. Despite this, the compounds were very active when they were tested in a Staphylococcus aureus murine thigh infection model. Compounds 1717 and 2144, given by oral gavage, resulted in 3- to 4-log decreases in the bacterial load compared to that in vehicle-treated mice, which was comparable to the results observed with the comparator drugs, vancomycin and linezolid. In summary, the research describes MetRS inhibitors with oral bioavailability that represent a class of compounds acting by a novel mechanism with excellent potential for clinical development. (Copyright © 2017 American Society for Microbiology.)
Databáze:	MEDLINE
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