Carole A. Bewley, Ph.D.

Research Goal

Our research seeks to discover and understand molecules that can prevent or treat infectious diseases. We focus on new antibiotics for drug-resistant bacteria, natural products with useful biological activities, and protein-based molecules that can block viral infection. By determining how these molecules work at the molecular level, we aim to identify new biological targets and provide a foundation for developing new approaches to prevent and treat infection.

Current Research

Our laboratory combines chemistry, biology, structural biology, and microbiology to study biologically active molecules and the processes they affect. Our research spans three closely connected areas: discovering natural products with useful biological activities, understanding how these molecules are made and how they work, and developing protein-based approaches to interfere with infection.

Natural Products and New Approaches to Antibiotic Discovery

Natural products are molecules produced by bacteria, fungi, plants, and other organisms. Many important medicines, including numerous antibiotics, originated from natural products. We search for previously unknown natural products and investigate compounds that act through unusual biological mechanisms. A major goal is to identify molecules that kill antibiotic-resistant bacteria, including compounds that act on targets not used by existing antibiotics. We also develop approaches for uncovering natural products that can be difficult to detect under standard laboratory conditions. These include methods for changing microbial growth conditions, analyzing complex mixtures of metabolites, and recognizing chemical features that can help prioritize previously unknown molecules for further study. Once a promising compound is identified, we determine its chemical structure, biological activity, cellular target, and mechanism of action. These studies can reveal both potential starting points for new therapeutics and previously unrecognized features of microbial biology.

How Microorganisms Make Biologically Active Molecules

Many natural products are produced through specialized biosynthetic pathways encoded in microbial genomes. We study the enzymes responsible for building and modifying these molecules to understand how complex natural products are assembled. This work includes studies of enzymes that form unusual chemical bonds, generate cyclic peptides and other constrained molecules, and control the final structures and biological activities of natural products. Understanding these processes can reveal new enzyme chemistry and may eventually allow useful molecules to be produced or modified in new ways.

Protein-carbohydrate Recognition and Antiviral Molecules

Carbohydrates, or glycans, cover the surfaces of cells and many infectious agents and play important roles in molecular recognition. Some viruses are surrounded by especially dense layers of glycans that can help shield them from the immune system. We study proteins that recognize these glycans and investigate whether this recognition can be used to prevent viral infection. One area of our research focuses on engineering carbohydrate-binding proteins and antibody-like molecules that bind viral surface proteins, block infection, and in some cases recruit immune mechanisms against infected cells. By determining how these proteins recognize their targets and how changes in their structure affect activity, we seek principles that can guide the design of more potent and durable antiviral molecules.

Understanding Molecular Structure and Mechanism

A recurring goal throughout our research is to understand why a biologically active molecule works. We use complementary structural, biochemical, genetic, and cellular approaches to determine the three-dimensional structures of molecules and proteins, identify their biological targets, and define the interactions responsible for activity. These studies help distinguish promising biological mechanisms from nonspecific effects and provide information that can guide subsequent therapeutic development.

Need for Further Study

Current questions include:

• Can antibiotic-resistant bacteria be killed by targeting biological processes that existing antibiotics do not exploit?
• Can we identify previously unknown natural products more efficiently and determine which are most likely to have useful biological activities?
• How do microorganisms construct structurally complex natural products, and can their biosynthetic machinery be used to generate new molecules?
• What determines whether small molecules can enter difficult-to-penetrate Gram-negative bacteria?
• How do carbohydrate-binding proteins achieve high specificity and potency?
• Can these principles be used to engineer protein-based molecules that prevent viral infection or help eliminate infected cells?

Research in Plain Language

Our lab studies molecules that may lead to new ways to prevent or treat infectious diseases. We focus on discovering natural products that can kill drug-resistant bacteria and on developing protein-based molecules that block viral infection, including HIV-1. We also investigate how these molecules work and how microorganisms produce them. This research addresses important challenges in human health, including antibiotic resistance and the continuing need for new ways to prevent and treat viral infections. By identifying new molecules, determining how they work, and uncovering biological processes that can be targeted therapeutically, we aim to provide new starting points for future medicines.