Bacterial tyrosine kinase inhibitors: a pathway to new antibiotics?

Research Project, 2026 – 2030

Bacterial protein tyrosine (BY) kinases are known to control exopolysaccharide (EPS) export in many bacteria, including pathogens. In bacteria, attenuation of protein-tyrosine phosphorylation occurs during oxidative stress. This drop in tyrosine phosphorylation has been observed in many bacteria but explained in only few. A recent study from my group (Shi et al. (2024) PNAS 118 : e2103377118) demonstrated that oxidative stress leads to partial unfolding of the formylmethionine deformylase DefA in B. subtilis. In this inactive state, DefA interacts with the active site of the BY-kinase PtkA and destabilizes its ATP-binding pocket. This leads to inhibition of kinase authophosphorylation and substrate phosphorylation. Due to the conserved architecture of BY-kinases, and wide-spread distribution of DefA homologues in bacteria, this mechanism might be conserved. We will test this in important pathogens: Staphylococcus aureus, Klebsiella pneumoniae and Streptococcus pneumoniae. Next, we will use structural/mechanistic knowledge and generative AI to devise peptides with the following properties: structure capable of mimicking DefA inhibition of BY-kinases, ability to cross bacterial membranes, extended half-life in the bacterial cytosol, zero interactions with human proteins. We will assess our synthetic inhibitors of BY-kinases for their capacity to destabilize biofilms and reduce infection potential of the selected pathogens on human cells in culture.