Combining chemistry with biology to investigate new ways of antibiotics discovery and development

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.

Bio

Growing up with an organic chemist as a father and a naturally creative mother, Dr. Carlson was introduced to the wonders of science at a young age. She recalls many Saturdays spent sitting on a stool at the lab bench, swirling beakers full of colored solutions and carefully examining the yield of her prized crystal growing kits. Her father was not only a researcher but also the owner of a small biotech company, and many of Dr. Carlson’s first and most influential introductions to science were spent with him. She long saw him thinking about problems related to the environment and human health, and it was largely due to her witnessing his passion and excitement for his work that she too decided to pursue a career in chemistry. Interestingly, perhaps also influenced by her father, Dr. Carlson’s sister is a scientist as well, and works as a ballistics specialist who deals with firearms at the Virginia State Crime Lab as “a different way of helping humankind.” Today, Dr. Carlson has formed a lasting collaboration with her father, and they continue to seek solutions to scientific challenges together.

The inspiration for the direction of her research program came much later, when Dr. Carlson traveled to other parts of the world and realized how desperately many people needed drugs that we often take for granted, such as penicillin. Some of the countries that inspired her most were Peru and India, where people she encountered on the streets were ailing from flesh eating bacterial infections and had a significantly lowered quality of life because they had no access to routine healthcare. There was a huge amount of work that needed to be done in this realm, and Dr. Carlson thus embarked on a journey as a chemist.

Another reason Dr. Carlson became a professor was to train a group of students who will ultimately do even greater things than she can do on her own. Focusing largely on graduate and undergraduate student education, Dr. Carlson is always looking to answer exciting questions in collaboration with her students.

Outside of research, Dr. Carlson enjoys photography. “The way I think about photography,” she says, “is not dissimilar to science, where you are trying to take what is in front of you and create a new way of thinking about it.” She continues, “A really powerful photographer takes an everyday image and makes something that allows you to see it like you have never seen it before. In science, that is critical -- you have to take facts that everyone already knows, but put them together in a new way that addresses challenges.”

For more information, visit http://www.chem.umn.edu/groups/carlson/

Awards

Sloan Research Fellowship, 2013

Cottrell Scholar Award, 2012

National Science Foundation CAREER Award, 2012

NIH Director's New Innovator Award, 2011

Pew Biomedical Scholar Award, 2010

Patents

United States Provisional Patent 61/944,235: "Design and Application of a Tag for Discovery of Natural Products Containing an Alkyne."

Carlson, E. E.; Trader, D. J.; Sidebottom, A. M. Filed February 25, 2014.

United States Provisional Patent 61/543,972: "Siloxyl Ether Reagents for Chemoselective Reaction with Carboxylic Acids."

Carlson, E. E.; Trader, D. J. Filed October 6, 2011.

U.S. Patent Number 9,079,983: "Chemoselective Enrichment for Compound Isolation."

Carlson, E. E.; Trader, D. J.; Odendaal, A. Y. Issued July 14, 2015.