Development of methionyl-tRNA synthetase inhibitors as antibiotics for Gram-positive bacterial infections [PublishAheadOfPrint]

Antibiotic resistant bacteria are widespread and pose a growing threat to human health. New antibiotics acting by novel mechanisms of action are needed to combat this threat. 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. Selective inhibitors, both previously published and new, were shown to be highly active on Gram positive bacteria with minimum inhibitory concentrations (MICs) ≤ 1.3 μg/mL against Staphylococcus, Enterococcus, and Streptococcus strains. Incorporation of radioactive precursors demonstrated the mechanism of activity was due to inhibition of protein synthesis. Little activity was observed against Gram-negative bacteria, consistent with Gram-negative species containing a different type of MetRS enzyme. The ratio of MIC to minimum bactericidal concentrations (MBC) was consistent with a bacteriostatic mechanism. Protein binding was high (>95%) for the compounds and this translated to a substantial increase in MICs when tested in the presence of plasma. Despite this, the compounds were very active when tested in the Staphylococcus aureus murine thigh infection model. Compounds 1717 and 2144 given by oral gavage resulted in 3-4-log decreases in bacterial load compared to vehicle-treated mice which was comparable to 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.

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