Due to the current lack of new antibacterial drugs and the continual evolution of microbial resistance, some fear that we have entered the “post-antibiotic era.” Traditional drug discovery methods cannot prevent the scourge of antibiotic resistance that is redefining the 21st century battle against emerging, recalcitrant infectious diseases on their own. Therefore, there is a significant need to expand on the strategies utilized in antibiotic discovery to include cross-disciplinary research. Dr. Erin E. Carlson, Associate Professor of Chemistry at the University of Minnesota, unites tools from chemistry and biology to explore and exploit the master regulators of microbial behavior and generate a deeper understanding of how to blind, silence, and eliminate bacteria. Her basic research thus has a tremendous potential for translational applications, that may help prevent the coming of the “post-antibiotic era,” and open up a new frontier in the next generation of antimicrobial therapeutic agents.

The interdisciplinary research between chemistry and biology presents extraordinary opportunities for antibiotic discovery and development. The Carlson Lab develops innovative tools for validating systems and generates many different assays for exploration of difficult protein targets. Small molecules developed in Dr. Carlson’s lab in collaboration with microbiologists will allow her and her team to perturb systems of interest in ways that weren’t possible using genetics or traditional biological manipulations. Possessing the unique ability to design molecules, the Carlson Lab is able to apply synthetic and medicinal chemistry, biochemistry and pharmacology, as well as molecular and cellular microbiology to elucidate and evade the mechanisms of antibiotic resistance.

Dr. Carlson’s group is pursuing three complementary research directions:

• Generate and apply methods for the characterization and inhibition of the primary bacterial signal transduction pathways: Histidine kinases are proteins involved in bacterial development, virulence, and antibiotic resistance, which act as mediators of how the bacteria sense and respond to their environment. When bacteria reach their target hosts, they initiate protocols to mount infections via histidine kinases, but these proteins are difficult to target because the tools available to study them are limited. Therefore, Dr. Carlson and her lab are developing novel methods to investigate and inhibit histidine kinases, hoping to find ways to blind the bacteria to their environment and thus prevent them from forming infections.
• Devise powerful strategies to explore and interpret the molecular language used by bacteria to respond to environmental and ecological cues: Millions of microbes reside in every environment and they naturally generate molecules to communication with one another. The Carlson Lab is interested in finding molecules, called natural products, that are used by bacteria to attenuate their neighbors’ ability to sense and respond to the environment. Natural products are recognized as privileged scaffolds due to their high propensity to interact with biological targets and are the source of ~75% of current treatments for infectious disease. Despite this, natural product discovery efforts have declined due to technical difficulties associated with detection, isolation and structural elucidation of minute quantities of complex molecular scaffolds. To revitalize these efforts, Dr. Carlson is developing an integrated discovery approach that combines mass spectrometry, informatics, and novel separation reagents to provide the foundation for continued characterization of the molecular dialogs between bacteria.
• Analysis of the multi-protein systems that dictate bacterial growth: In this basic research project, Dr. Carlson takes the drugs that have been clinically in use for many years to generate new probes and explore the process of bacterial growth and resistance. Bacteria are surrounded by a cell wall composed of a complex peptidoglycan structure that is essential for survival. Although the proteins required for construction of peptidoglycan, including the penicillin-binding proteins, are the target for many antibiotics, its structure and assembly are only partially understood. By designing and applying chemical probes to characterize the penicillin-binding proteins, Dr. Carlson hopes to further understand the biochemical pathways implicated in bacterial growth and pathogenicity.