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J Biol Chem. 2018 Jun 15;293(24):9506-9519. doi: 10.1074/jbc.RA118.002592. Epub 2018 May 2.

Methionine biosynthesis and transport are functionally redundant for the growth and virulence of Salmonella Typhimurium.

Author information

1
From the Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria 3000, Australia.
2
From the Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria 3000, Australia, nancyw@unimelb.edu.au.
3
the Department of Biochemistry and Molecular Biology, University of Melbourne at the Bio21 Institute, Parkville, Victoria 3052, Australia.
4
the Institute of Integrative Biology, University of Liverpool, Liverpool L69 7ZB, United Kingdom.
5
the School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales 2052, Australia, and.
6
the Department of Microbiology, Monash University, Clayton, Victoria 3800, Australia.
7
From the Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria 3000, Australia, rastru@unimelb.edu.au.

Abstract

Methionine (Met) is an amino acid essential for many important cellular and biosynthetic functions, including the initiation of protein synthesis and S-adenosylmethionine-mediated methylation of proteins, RNA, and DNA. The de novo biosynthetic pathway of Met is well conserved across prokaryotes but absent from vertebrates, making it a plausible antimicrobial target. Using a systematic approach, we examined the essentiality of de novo methionine biosynthesis in Salmonella enterica serovar Typhimurium, a bacterial pathogen causing significant gastrointestinal and systemic diseases in humans and agricultural animals. Our data demonstrate that Met biosynthesis is essential for S. Typhimurium to grow in synthetic medium and within cultured epithelial cells where Met is depleted in the environment. During systemic infection of mice, the virulence of S. Typhimurium was not affected when either de novo Met biosynthesis or high-affinity Met transport was disrupted alone, but combined disruption in both led to severe in vivo growth attenuation, demonstrating a functional redundancy between de novo biosynthesis and acquisition as a mechanism of sourcing Met to support growth and virulence for S. Typhimurium during infection. In addition, our LC-MS analysis revealed global changes in the metabolome of S. Typhimurium mutants lacking Met biosynthesis and also uncovered unexpected interactions between Met and peptidoglycan biosynthesis. Together, this study highlights the complexity of the interactions between a single amino acid, Met, and other bacterial processes leading to virulence in the host and indicates that disrupting the de novo biosynthetic pathway alone is likely to be ineffective as an antimicrobial therapy against S. Typhimurium.

KEYWORDS:

S-adenosylmethionine (SAM); Salmonella enterica; biosynthesis; in vivo infection; methionine; peptidoglycan; transporter; virulence

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