Pantetheinamides that inhibit the growth of intracellular Salmonella Typhimurium

The metabolic adaptability of intracellular pathogens, such as the Gram-negative Salmonella enterica serovar Typhimurium (STm), enables their survival in nutrient-restricted host environments, while also presenting an opportunity for selective antimicrobial targeting. Herein, we report the synthesis and screening of a small pantetheinamide library aimed at inhibiting the proliferation of STm within macrophages. Two lead compounds exhibited selective activity against intracellular STm and reduced bacterial burden in a murine colitis model. Mechanistic studies suggest their primary mode of action to be the inhibition of coenzyme A (CoA) biosynthesis via the PanD-PanZ regulatory complex, which is absent in host cells. Importantly, resistance pressure to our compound was shown to be significantly stronger in nutrient-limited media compared to nutrient-rich media, supporting the targeting of nutrient stress as a strategy to delay resistance. This work highlights the value of inhibiting pathogen-specific metabolic vulnerabilities in combination with host defence mechanisms to develop novel antimicrobials.