Amino acid decarboxylation preserves <i>Salmonella</i> fitness during phagocyte-derived oxidative stress

Salmonellae have been causing disease in humans since at least the Neolithic Revolution, yet non-typhoidal Salmonella infections remain a significant public health challenge. The success of <i>Salmonella</i> as a pathogen stems, in part, from its ability to subvert and survive the host response of macrophages. The amino acid L-arginine is critical for Salmonella enterica serovar Typhimurium virulence and resistance to reactive oxygen species produced by the phagocyte NADPH oxidase. The precise mechanisms by which L-arginine fosters oxidative stress resistance have remained unclear. In this report, we demonstrate that Salmonella relies on the proton-consuming decarboxylation of L-arginine and ornithine to promote resistance against the acute cytotoxicity emanating from the phagocyte NADPH oxidase. On the other hand, polyamines synthesized downstream of L-arginine and ornithine decarboxylation aid in the recovery phase. Our findings redefine the physiological role of amino acid decarboxylation, establishing it as a critical defense mechanism against oxidative stress that is functionally distinct from polyamine biosynthesis. By disentangling the regulatory and functional roles of individual decarboxylases, our study clarifies a long-standing ambiguity in the field and highlights how <i>Salmonella</i> exploits complementary metabolic pathways during its adaptation to oxidative stress in the host.