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首页> 外文期刊>Antimicrobial agents and chemotherapy. >Amino Acid Biosynthetic Pathways Are Required for Klebsiella pneumoniae Growth in Immunocompromised Lungs and Are Druggable Targets during Infection
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Amino Acid Biosynthetic Pathways Are Required for Klebsiella pneumoniae Growth in Immunocompromised Lungs and Are Druggable Targets during Infection

机译：氨基酸生物合成途径是免疫肺部肺部肺炎肺炎的生长所必需的，并且在感染期间是可用的靶标

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摘要

The emergence of multidrug-resistant Klebsiella pneurnoniae has rendered a large array of infections difficult to treat. In a high-throughput genetic screen of factors required for K. pneurnoniae survival in the lung, amino acid biosynthesis genes were critical for infection in both immunosuppressed and wild-type (WT) mice. The limited pool of amino acids in the lung did not change during infection and was insufficient for K. pneurnoniae to overcome attenuating mutations in aroA, hisA, leuA, 1euB, serA, serB, trpE, and tyrA in WT and immunosuppressed mice. Deletion of aroA, which encodes 5-enolpyruvylshikimate-3-phosphate (EPSP) synthase class I, resulted in the most severe attenuation. Treatment with the EPSP synthase-specific competitive inhibitor glyphosate decreased K. pneurnonioe growth in the lungs. K. pneurnoniae expressing two previously identified glyphosate-resistant mutations in EPSP synthase had significant colonization defects in lung infection. Selection and characterization of six spontaneously glyphosate-resistant mutants in K. pneurnoniae yielded no mutations in aroA. Strikingly, glyphosate treatment of mice lowered the bacterial burden of two of three spontaneous glyphosate-resistant mutants and further lowered the burden of the less-attenuated EPSP synthase catalytic mutant. Of 39 clinical isolate strains, 9 were resistant to glyphosate at levels comparable to those of selected resistant strains, and none appeared to be more highly resistant. These findings demonstrate amino acid biosynthetic pathways essential for K. pneumoniae infection are promising novel therapeutic targets.
机译：多药物抗性的克雷布耳的出现难以治疗大量感染。在肺中k.肺炎群生存所需的因素的高通量遗传筛选中，氨基酸生物合成基因对于免疫抑制和野生型（WT）小鼠的感染至关重要。在感染过程中，肺中氨基酸的有限池不发生变化，并且K.活塞不足，以克服aroa，hisa，leua，1eub，血清，塞培，trpe和泰拉中的衰减突变在wt和免疫抑制的小鼠中。缺失aroa，其编码5-烯醇吡咯伏太阳极-3-磷酸盐（EPSP）合成酶I，导致最严重的衰减。用EPSP合成酶特异性竞争性抑制剂草甘膦治疗降低K.肺中的活血生长。 K.表达两种先前鉴定的EPSP合酶抗性抗性突变的活塞膜具有显着的肺部感染缺陷。在K.Pneurnoniae中的六种自发性草甘膦抗突变体的选择和表征在aroa中没有产生突变。尖锐的是，草甘膦治疗小鼠的治疗降低了三种自发性草甘膦抗突变体中的两种细菌负荷，进一步降低了较低的EPSP合酶催化突变体的负担。在39例临床中间菌株中，9株对与选定抗性菌株相当的水平的含量抗性，并且没有似乎更高的抗性。这些发现表明氨基酸生物合成途径对于K.肺炎肺炎感染是有前途的新疗法靶标。

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