DksA inhibitors against intracellular and persistent Salmonella are effective in acute models of infection
- Ju-Sim Kim
- Vijay Kumar
- Lin Liu
- Yu J. Choi
- Simona Senovaityte
- Bruce D. McCollister
- Nathan Wlodarchak
- David J. Orlicky
- Peter J. Rice
- Shaodong Dai
- Michael F. Wempe
- Andrés Vázquez-Torres
2026-03-18
We are in dire need of antibiotics endowed with new mechanisms of action. The DksA protein regulates the transcription of genes involved in metabolism, translation, and virulence in Gram-negative bacteria. DksA is evolutionarily conserved among Gram-negative pathogens but is absent in humans. Here, we identified a conserved acidic pocket at the tip of the coiled-coil domain of DksA that is amenable for drug development. Our bioinformatics and experimental approaches identified N -(3,4-dimethoxyphenyl)-1H-1,2,4-triazole-3-carboxamide as a DksA inhibitor with moderate antimicrobial activity. Derivatization of the dimethoxyphenyl functionality and aliphatic linker of N -(3,4-dimethoxyphenyl)-1H-1,2,4-triazole-3-carboxamide generated several new chemical entities with excellent IC 50 values against DksA-regulated in vitro transcription and improved antimicrobial activity against Salmonella and several other Gram-negative bacteria. Our pharmacokinetic and pharmacodynamic evaluations indicate that the N -(4-phenylbutyl)-1H-1,2,4-triazole-3-carboxamide analog is absorbed in the gastrointestinal tract of rats and is distributed into viscera. The systemic administration of the N -(4-phenylbutyl)-1H-1,2,4-triazole-3-carboxamide analog protected mice against oral and systemic Salmonella infections while practically preventing the formation of microabscesses and necrotic foci in Salmonella -infected mice. Our investigations have identified a previously unknown class of antibiotics against the transcriptional regulator DksA that is endowed with antimicrobial activity against Gram-negative pathogens.