Department of Medicine, University of Washington, Seattle, Washington, USA.
Department of Biochemistry, University of Washington, Seattle, Washington, USA.
Antimicrob Agents Chemother. 2017 Oct 24;61(11). doi: 10.1128/AAC.00999-17. Print 2017 Nov.
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 , , and 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 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.
耐药菌广泛存在，对人类健康构成日益严重的威胁。需要新型抗生素来应对这一挑战，这些抗生素需要通过新的作用机制发挥作用。细菌甲硫氨酰-tRNA 合成酶（MetRS）是蛋白质合成所必需的酶，革兰氏阳性菌中的 MetRS 与哺乳动物细胞质中的 MetRS 有很大的不同。已发表的和新的选择性抑制剂都显示出对革兰氏阳性菌有很高的活性，MIC 值均≤1.3μg/ml，对 、 和 菌株有效。放射性前体的掺入表明，其作用机制是由于抑制了蛋白质合成。对革兰氏阴性菌的活性观察到很少，这与革兰氏阴性菌种含有不同类型的 MetRS 酶的事实一致。MIC 与最低杀菌浓度（MBC）的比值与抑菌机制一致。化合物的蛋白结合率很高（>95%），当在含有血清的情况下进行测试时，化合物的 MIC 值会显著升高。尽管如此，在 鼠大腿感染模型中进行测试时，这些化合物仍非常有效。经口服灌胃给予化合物 1717 和 2144，与用载体处理的小鼠相比，细菌载量减少了 3-4 个对数级，与比较药物万古霉素和利奈唑胺的结果相当。总之，该研究描述了具有口服生物利用度的 MetRS 抑制剂，这些抑制剂代表了一类通过新型作用机制发挥作用的化合物，具有很好的临床开发潜力。
