2025/10/28 by Jacob Pierscianowski, Dustin Duncan, Chunling Blue Lan +17 · 1 voice
Neuroscience · Energy · Biochemistry, Genetics and Molecular Biology · #Neurological diseases and metabolism #Metalloenzymes and iron-sulfur proteins #Coenzyme Q10 studies and effects
paper · doi:10.1101/2025.10.28.685111
openalex publication_date 2025/10/28 · openalex created_date 2025/10/29 · openalex updated_date 2026/07/15
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.