Methionine Biosynthesis and Transport Are Functionally Redundant for the Growth and Virulence of Typhimurium

Methionine (Met) is an amino acid essential for many important cellular and biosynthetic functions, including the initiation of protein synthesis and -adenosylmethionine-mediated methylation of proteins, RNA, and DNA. The 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 methionine biosynthesis in 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 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 Typhimurium was not affected when either Met biosynthesis or high-affinity Met transport was disrupted alone, but combined disruption in both led to severe growth attenuation, demonstrating a functional redundancy between biosynthesis and acquisition as a mechanism of sourcing Met to support growth and virulence for Typhimurium during infection. In addition, our LC-MS analysis revealed global changes in the metabolome of 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 biosynthetic pathway alone is likely to be ineffective as an antimicrobial therapy against Typhimurium.