Small proteins and peptides play an outsized role in biology. They act as antibacterials, signaling factors of our immune, endocrine, and central nervous system, and are foundational in microbial community and bacteria-host interactions. However, finding and characterizing small proteins and peptides is challenging. Their small size often leaves them overlooked in genomic studies and makes them hard to isolate from natural sources or produce synthetically. These challenges have resulted in relatively few small proteins and peptides being discovered and characterized despite the vast numbers predicted. This lack of knowledge prevents us from understanding the functional diversity of unrecognized masses of small proteins and peptides that could defend against pathogen invasion and influence host cell functions. We are developing principles and tools to uncover, study, and deliver natural and synthetic small proteins and peptides that control bacterial growth and communication, and amplify beneficial host interactions. Current projects include:
Uncovering microcin diversity and functions
Microcins are potent and selective small protein antibacterials used in microbial competition. However, they have been challenging to identify and only 15 have been discovered in E. coli and its close relatives. We are developing high throughput computational and experimental screening methods to uncover and characterize the diversity of microcins across Gram-negative bacteria. We are discovering their unique mechanisms of action, rare ability to translocate across bacterial membranes, host interactions, and developing cell-based systems to deliver them to fight infection.
Discovering synthetic peptide antibiotics
Natural macrocyclic peptide products have provided novel antibiotic scaffolds targeting many essential bacterial processes. But discovery of new natural products remains slow. The generation and screening of comprehensive sequence libraries is the most thorough means to study peptides. We are combining new molecular screening platforms with machine learning approaches to speed the discovery processes to expand our knowledge of antibacterial macrocyclic peptides and understand how their sequence controls their activity.
Developing bacterial display and secretion systems
The discovery and implementation of bioactive peptides and small proteins requires advancement in computational and experimental screening. We are developing bioinformatic tools to improve the discovery process and bacterial display and secretion systems to uncover bioactive peptides and small proteins across natural and synthetic sequence space.
Designing bacteria-host interactions
Bacteria can colonize every niche of our bodies. We design systems that enable bacteria to display and release bioactive small proteins and peptides to target other microbes and to interact with the host. Through testing of delivery bacteria and bioactive proteins we are discovering combinations that allow us to influence bacteria populations and host responses across the body.
Investigating antibacterial nanobodies
Antibodies are well known for their ability to selectively bind bacteria. But the identification of directly antibacterial antibodies has been elusive. We are developing a small and single-chain class of antibodies called nanobodies to target and/or directly kill specific bacteria. We are selecting and enhancing scaffolds to support these activities and investigating potential bacterial targets.