Discovery and antibacterial study of potential PPK1 inhibitors against uropathogenic E. coli

Area of Science:

• Microbiology and Infectious Diseases
• Drug Discovery and Development
• Molecular Biology

Background:

• Multi-drug resistant bacteria, particularly uropathogenic *Escherichia coli*, pose a significant threat, necessitating novel antibacterial strategies.
• Urinary tract infections (UTIs) are common and often caused by resistant bacterial strains.
• The PPK1 kinase is crucial for virulence in uropathogenic *E. coli*, regulating motility, biofilm formation, and quorum sensing.

Purpose of the Study:

• To identify and characterize novel small molecules that inhibit the PPK1 kinase.
• To evaluate the efficacy of these compounds against uropathogenic *E. coli* in vitro and in vivo.
• To explore a new chemotype for developing antibacterials targeting PPK1.

Main Methods:

• Virtual screening was employed to identify potential PPK1 inhibitors.
• Biological assays were conducted to validate compound activity.
• In vitro and in vivo studies assessed the compounds' effects on bacterial biofilm formation, invasion, oxidative stress resistance, and efficacy in a mouse UTI model.

Main Results:

• Two small molecules targeting PPK1 were successfully identified.
• These compounds demonstrated the ability to disrupt uropathogenic *E. coli* biofilm formation.
• The identified molecules reduced bacterial invasive ability and resistance to oxidative stress, showing significant antibacterial activity in a mouse UTI model.

Conclusions:

• The discovered small molecules effectively inhibit PPK1, a key virulence factor in uropathogenic *E. coli*.
• These compounds represent a promising new chemotype for developing novel antibacterial agents against drug-resistant UTIs.
• Targeting PPK1 offers a viable strategy to combat infections caused by multi-drug resistant bacteria.