Abstract

Polyamines integrate metabolism with innate immunity; however, their antibacterial roles remain unresolved. Here, we show that spermine suppresses innate immune responses against Salmonella enterica serovar Typhimurium infection in macrophages. Exogenous spermine blunted pro-inflammatory responses and increased intracellular bacterial burden in vitro and in vivo. Pharmacologic depletion or back-conversion of endogenous polyamines enhanced pro-inflammatory responses, revealing an intrinsic brake. Mechanistically, spermine promoted B-to-Z conformational switching of bacterial genomic DNA, which attenuated cGAS-STING activation; chloroquine or cerium chloride modulations validated DNA topology control. Genetic and pharmacologic dissection indicated that either TLR4 or cGAS-STING is sufficient for spermine’s suppression, whereas their combined blockade abolished it. These findings highlight coordinated immune evasion at the metabolism-DNA interface, offering therapeutic targets for infection control.