Peptide-based inhibitors of histidine kinases to fight drug-resistant pathogens – PIHKpath

Resistance to antibiotics is a main threat for human health. New drugs and treatment strategies are urgently needed. Ideal next generation antibiotics will interfere with bacterial virulence or with the resistance mechanisms restoring the bacteria sensitivity towards a given antibiotic. We have recently characterized two bacterial-produced peptide natural products, which exhibit both desired effects in pathogenic enterococci and Staphylococcus aureus.
Mode-of-action analyses showed that these peptides inhibit certain histidine kinases (HKs) that control virulence and antibiotic resistance in these pathogens, which highlights their potential as HKs inhibitors. The fact that HKs are absent in eukaryotic cells and control a wide range of bacterial behaviors such as virulence, biofilm formation, antibiotic resistance, and that some HKs are essential make them highly attractive drug targets.
By a multidisciplinary approach combining microbiology, structural biology, biochemistry, chemical biology and molecular biology, this project aims to understand the scope of HK inhibition and gain structural insights into such inhibition by these peptides in Gram-positive pathogens, which will guide peptide engineering towards the generation of new molecules with modulated activities.