Douglas A. Mitchell, Ph.D.

Genome-guided discovery and engineering of macrocyclic peptides

Research Keywords: natural products, macrocyclic peptides, ribosomally synthesized and post-translationally modified peptides (RiPPs), genome mining, biosynthetic enzymology, synthetic biology, directed evolution, AI-guided design

Research Specialty: Chemical biology of RiPP biosynthesis and macrocyclic peptide engineering

Research Description: Microorganisms encode vast numbers of peptide natural products that are synthesized on the ribosome and then remodeled by enzymes into constrained, highly functional molecules. The Mitchell lab studies how these biosynthetic enzymes recognize precursor peptides, install unusual peptide backbone modifications, and generate macrocyclic architectures such as lasso peptides, pyritides, and related RiPP scaffolds.

The lab integrates bioinformatics, biochemistry, structural biology, synthetic biology, cell-free biosynthesis, and protein engineering to discover new natural products, define the mechanisms of their assembly, and build new-to-nature peptide scaffolds with useful biological functions. This work spans fundamental studies of enzyme mechanism and molecular recognition, as well as translational efforts directed toward infectious disease, cancer, metabolic disease, and central nervous system drug delivery.

The Mitchell lab is dedicated to understanding the rules that govern peptide natural product biosynthesis and to using those rules to create programmable macrocycles with tunable conformations, target selectivity, and favorable stability properties.

Current projects in the lab include:

1. Discovery of new RiPP biosynthetic pathways and natural products using genome-mining platforms, metagenomic analysis, and high-throughput prioritization tools
2. Mechanistic characterization of biosynthetic enzymes that mediate precursor peptide recognition and unusual peptide backbone chemistry
3. Development of cell-free, robotic, and chemoenzymatic platforms to access cryptic or silent natural products that are difficult to obtain by conventional methods
4. Engineering of lasso peptides, pyritides, and related macrocycles as programmable scaffolds for therapeutic and diagnostic applications
5. AI-guided design and directed evolution of constrained peptides that engage targets such as GPCRs, integrins, and blood-brain barrier transport systems
6. Discovery of antimicrobial macrocycles and related agents targeting Gram-negative bacterial outer membrane proteins and other challenging biological targets

We use a multidisciplinary approach that includes bioinformatics, enzymology, chemical biology, synthetic biology, structural biology, mass spectrometry, and protein engineering. The lab is part of the Vanderbilt Institute of Chemical Biology and collaborates broadly across chemistry, biochemistry, microbiology, and translational biomedical research.

Significance: Peptide natural products occupy an important middle ground between small molecules and biologics. Their conformational constraints can produce high target affinity, selectivity, proteolytic stability, and access to modes of molecular recognition that are often difficult to achieve with conventional therapeutic modalities. At the same time, microbial genomes encode far more of these molecules than are currently known, leaving a large reservoir of unexplored chemical and functional diversity.

By determining how nature builds these scaffolds and by developing tools to discover and reprogram them, the Mitchell lab aims to expand accessible chemical space for both basic science and therapeutic development. This work provides new insight into enzyme function, microbial molecular recognition, and natural product biosynthesis, while also enabling the development of new leads for antibiotic discovery, cancer therapy, metabolic disease, and drug delivery to the central nervous system.

Postdoctoral Position Availability and Details: Prospective postdoctoral candidates with interests in chemical biology, enzymology, bioinformatics, synthetic biology, structural biology, and peptide therapeutics should follow the instructions listed on our website (link: https://lab.vanderbilt.edu/mitchell-lab/contact/)

Google Scholar Listing of Dr. Mitchell’s Publications