# DksA inhibitors against intracellular and persistent Salmonella are effective in acute models of infection

## TL;DR

Researchers developed new antibiotics targeting the DksA protein in Salmonella, which effectively treat infections in mice.

## Contribution

A new class of DksA inhibitors with antimicrobial activity against Gram-negative bacteria was identified.

## Key findings

- N-(4-phenylbutyl)-1H-1,2,4-triazole-3-carboxamide protected mice from Salmonella infections.
- The compound showed improved antimicrobial activity and inhibited DksA-regulated transcription.
- It was absorbed in the gastrointestinal tract and distributed into viscera in rats.

## Abstract

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 IC50 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.

Antibiotics against the DksA transcription factor of Gram-negative rods protect mice from oral and systemic Salmonella infection.