Amino Acid Biosynthetic Pathways Are Required for Klebsiella pneumoniae Growth in Immunocompromised Lungs and Are Druggable Targets during Infection.

Autor:	Silver RJ; Graduate Program in Immunology, MERGE-ID Track, Sackler School of Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts, USA., Paczosa MK; Graduate Program in Immunology, MERGE-ID Track, Sackler School of Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts, USA., McCabe AL; Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, Massachusetts, USA., Balada-Llasat JM; Department of Pathology, The Ohio State Wexner Medical Center, Columbus, Ohio, USA., Baleja JD; Department of Developmental, Molecular, and Chemical Biology, Tufts University School of Medicine, Boston, Massachusetts, USA., Mecsas J; Graduate Program in Immunology, MERGE-ID Track, Sackler School of Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts, USA joan.mecsas@tufts.edu.; Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, Massachusetts, USA.
Jazyk:	angličtina
Zdroj:	Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2019 Jul 25; Vol. 63 (8). Date of Electronic Publication: 2019 Jul 25 (Print Publication: 2019).
DOI:	10.1128/AAC.02674-18
Abstrakt:	The emergence of multidrug-resistant Klebsiella pneumoniae has rendered a large array of infections difficult to treat. In a high-throughput genetic screen of factors required for K. pneumoniae 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. pneumoniae to overcome attenuating mutations in aroA , hisA , leuA , leuB , 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. pneumoniae growth in the lungs. K. pneumoniae 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. pneumoniae 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. (Copyright © 2019 American Society for Microbiology.)
Databáze:	MEDLINE
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