Functions and Mechanisms of Bacterial Ser/Thr Kinases

This research seeks to elucidate the fundamental role of post-translational protein modifications in bacterial cellular signaling. To adapt to environmental changes, bacteria must rapidly sense and respond to stimuli in order to appropriately modify their cellular physiology. To achieve this, bacteria have evolved intricate signaling networks to maintain homeostasis under stress conditions, including those that promote evasion of host immune responses and resistance to antibiotics. One subset of these systems are serine-threonine (S/T) and serine-threonine-tyrosine (S/T/Y) kinases, which have been shown to be critical, and often essential, for bacterial growth and division, antibiotic resistance, virulence, and biofilm formation. Members of this group include the highly conserved Hanks-type eukaryotic-like penicillin-binding and serine-threonine associated (PASTA) kinases that are found almost exclusively in single copy across Gram-positive bacteria and regulate a wide range of physiological processes, including carbon metabolism, cell signaling, peptidoglycan biosynthesis, virulence, and biofilm formation. As such, PASTA kinases and their transduction pathways represent attractive targets for novel antimicrobials, however these signaling systems remain poorly understood. Non-Hanks-type S/T and S/T/Y kinases have also been shown to be important determinants for resisting oxidative, pH, and osmotic stress, yet the molecular mechanisms underlying these phenotypes and the regulation of these signaling systems remain unknown. The long-term goal of my laboratory is to explore how bacteria employ post- translational modifications to fine-tune their cellular physiology and how multiple transduction pathways are coordinated and integrated to respond to environmental changes. Such information is essential to understand bacterial contributions to human health and disease. To do so, we propose to combine complementary biochemical, genetic, and proteomic approaches to 1) define the PASTA kinase signal cascades and metabolic rewiring that enables bacteria to resist cell envelope stress, 2) decipher the role of non-Hanks-type S/T and S/T/Y kinases in bacterial stress responses, and 3) understand how bacteria integrate signals across multiple kinase signaling pathways to produce a coordinated physiological response. Results of the proposed experiments will advance knowledge of how bacteria sense and respond to environmental stimuli and ultimately inform efforts to develop new antimicrobial therapies targeting bacterial signal transduction systems. Project Number: 1R35GM162139-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: Caroline Grunenwald | Institution: UNIVERSITY OF MISSOURI-COLUMBIA, COLUMBIA, MO | Award Amount: $427,526 | Activity Code: R35 | Study Section: Maximizing Investigators' Research Award - F Study Section[MRAF] View on NIH RePORTER: https://reporter.nih.gov/project-details/11269908