A new study from Oregon Health & Science University has uncovered how small molecules within bacteria interact with proteins, revealing a network of molecular connections that could improve drug discovery and cancer research.
The work also highlights how methods and principles learned from bacterial model systems can be applied to human cells, providing insights into how diseases like cancer emerge and how they might be treated. The results are published today in the journal Cell.
The multi-disciplinary research team, led by Andrew Emili, Ph.D., professor of systems biology and oncological sciences in the OHSU School of Medicine and OHSU Knight Cancer Institute, alongside Dima Kozakov, Ph.D., professor at Stony Brook University, studied Escherichia coli, or E. coli, a simple model organism, to map how metabolites — small molecules essential for life — interact with key proteins such as enzymes and transcription factors. These interactions control important processes such as cell growth, division and gene expression, but how exactly they influence protein function is not always clear.
The team used advanced tools like chemo-proteomics — developed in the Emili lab — and artificial intelligence-driven structural modeling — developed by the Kozakov lab — to identify nearly 300 ligands, which are molecules, and their binding sites on bacterial proteins critical for the bacteria's survival.
Although this study centered on E. coli, its implications stretch far beyond microbes.
"E. coli was just an easy model system for us to work out the kinks," Emili said.
"Microbes are important — they're the predominant life form on Earth — but what we've learned and the toolkit we've built can be generalized to other systems, like humans. And that's where this work becomes particularly exciting."
The findings are especially relevant to cancer research, where metabolism in tumor cells is often drastically altered compared with normal cells.
"In cancer cells, metabolism is remarkably changed," Emili said. "People don't necessarily think about the molecular consequences of that dysregulation. Our work in E. coli shows that small molecules interact dynamically with many proteins inside cells and change their behavior. In cancer cells, these interactions could be major drivers of tumor growth, proliferation and potentially even immune evasion."
This realization opens new possibilities for targeting cancer. Small molecules might influence how transcription factors are activated, potentially altering gene expression programs and reshaping the cancer cell's biology. By understanding these interactions, the researchers hope to identify vulnerabilities in cancer cells that can be exploited for treatment.
Systematic approach
The study's methodology also challenges traditional drug discovery processes, which often involve screening massive chemical libraries to identify compounds that affect proteins. Instead, this research focuses on identifying the native ligands that proteins naturally prefer to bind.
"We're kind of turning the process on its head," Emili said. "Instead of screening randomly, we're systematically finding the small molecules that proteins intrinsically like to bind to. This gives us a logical starting point for drug development."
Using AI machine learning powered by the Department of Energy's Frontier, one of the world's fastest supercomputers, the team mapped how small molecules bind to proteins at specific sites. This atomic-level structural precision allows scientists to design synthetic compounds that bind similarly but more tightly, either enhancing or blocking the protein's function.
"For cancer, this means we could develop small molecules that bind to transcription factors, protein kinases or other targets that are dysregulated in tumor cells, but this is also applicable to other diseases such as neurodegeneration, cardiovascular conditions and metabolic disorders like diabetes," Emili said.
Beyond cancer, the study has implications for antibiotics and understanding the human microbiome. Many bacteria express similar proteins that share conserved binding sites, meaning insights from this study could help design drugs that target harmful pathogens without harming beneficial microbes.
"By identifying natural compounds that bind to a range of essential regulatory proteins, this work may lead to the discovery of new antimicrobial drug targets and the design of therapies that better modulate protein activity in infected cells and tissues," Emili said.
Emili's background is as a systems biologist and in functional proteomics — exploring the roles proteins play in cellular processes. His hope is by collaborating with researchers in the OHSU Knight Cancer Institute, his expertise can be used in assisting with drug discovery, particularly the early interception of cancer before it becomes too advanced to treat.
"This is what drug discovery is about," Emili said.
"We're learning how small molecules bind to proteins, and from there, we can guide the rational development of therapeutic compounds. It's discovery-driven science leading to real-world applications."
In addition to Emili and Kozakov, collaborating researchers from Boston University and the University of Toronto contributed to this study. A full list of the authors is available here.
This study was supported by the National Institutes of Health grants S10OD026807, RM1GM135136, R01GM140098, and R35GM118078, the National Science Foundation grant DMS-2054251, the Canadian Institutes of Health Research awards MOP-106449 and MOP-159677, the Natural Sciences and Engineering Research Council of Canada award DG-20234, and via infrastructure support from the Canada Foundation for Innovation, and computer time provided by the INCITE program. This research also used resources of the Oak Ridge Leadership Computing Facility at the Oak Ridge National Laboratory, which is supported by the Office of Science of the U.S. Department of Energy under Contract No. DE-AC05-00OR22725. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funders.
