Do Shoot the Messenger: PASTA Kinases as Virulence Determinants and Antibiotic Targets

All domains of life utilize protein phosphorylation as a mechanism of signal transduction. In bacteria, protein phosphorylation was classically thought to be mediated exclusively by histidine kinases as part of two-component signaling systems. However, it is now well appreciated that eukaryotic-like serine/threonine kinases (eSTKs) control essential processes in bacteria. A subset of eSTKs are single-pass transmembrane proteins that have extracellular penicillin-binding-protein and serine/threonine kinase-associated (PASTA) domains which bind muropeptides. In a variety of important pathogens, PASTA kinases have been implicated in regulating biofilms, antibiotic resistance, and ultimately virulence. Although there are limited examples of direct regulation of virulence factors, PASTA kinases are critical for virulence due to their roles in regulating bacterial physiology in the context of stress. This review focuses on the role of PASTA kinases in virulence for a variety of important Gram-positive pathogens and concludes with a discussion of current efforts to develop kinase inhibitors as novel antimicrobials. In addition to traditional two-component systems, phosphorylation by eukaryotic-like ser/thr kinases (eSTKs) has emerged as a key signal transduction system in bacteria. PASTA kinases have emerged as a highly conserved subset of eSTKs that sense muropeptides in Firmicutes and Actinobacteria. Recent studies demonstrate that both broadly conserved and species-specific functions of PASTA kinases connect metabolism and cell-wall homeostasis to virulence and antibiotic resistance. Advances in proteomics have led to the identification of many phosphosubstrates; however, the functional consequences of phosphorylation in many cases remain unknown. Due to their conserved role in virulence and antibiotic resistance, PASTA kinases have emerged as high-value targets for antibiotic development.