WalK, the path towards new antibacterials with low potential for resistance development

Resistance to antibiotics used in the treatment of bacterial infectious diseases is a global health problem. More than a decade ago, two-component systems such as WalKR were proposed as ideal targets for the development of new antibiotics. Biochemical screens for WalKR inhibitors using compound libraries have identified many hits, some of which were shown to have non-specific effects. The recently published structures of the S. mutans and B. subtilis WalK provide the opportunity to study inhibitors of WalK autophosphorylation at the atomic level and means to design compounds with improved specificity and affinity using a structure-based approach.