Pantetheinamides that inhibit the growth of intracellular Salmonella Typhimurium

Pierscianowski, J.; Duncan, D.; Lan, C.; Kholiya, R.; Diaconescu-Grabari, S.; Chowdhury, F. R.; Abdelaal, A. B.; Chang, A.; Roe, I.; Heans Moreyra, S.; Campbell, S.; Pierret, A.; Adhikari, K.; Ghosh, S.; Pistofidis, A.; Behr, M.; Schmeing, M.; Findlay, B.; Lupien, A.; Auclair, K.

doi:10.1101/2025.10.28.685111

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bioRxiv · 10.1101/2025.10.28.685111

Pantetheinamides that inhibit the growth of intracellular Salmonella Typhimurium

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Abstract

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.

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Pierscianowski, J., Duncan, D., Lan, C., Kholiya, R., Diaconescu-Grabari, S., Chowdhury, F. R., Abdelaal, A. B., Chang, A., Roe, I., Heans Moreyra, S., Campbell, S., Pierret, A., Adhikari, K., Ghosh, S., Pistofidis, A., Behr, M., Schmeing, M., Findlay, B., Lupien, A., Auclair, K.. 2025-10-28. Pantetheinamides that inhibit the growth of intracellular Salmonella Typhimurium. https://doi.org/10.1101/2025.10.28.685111

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