Fischbach joins project to generate drugs from bacterial genomes

Bacteria generate small molecules to fend off their fellow microbes. They also produce molecules that affect the response of host organisms—including humans—to their presence. Such molecules have been a major source of antibiotics, immunosuppressants, anti-cancer agents, and other drugs. But their discovery has not been systematic and the products of bacteria living in our bodies have only recently drawn scientific notice.

However, thanks to genome sequencing, there are now databases containing the blueprints (sequences) of 160 million genes from nearly a quarter-million organisms, including the genes of bacteria species that live in and interact with us—the human microbiome. These bacterial genes encode molecules that could yield narrow-spectrum antibiotics, immune system regulators, and neuroactive drugs. But first scientists must find the potentially therapeutic needles in this genomic haystack.

Research in the laboratory of Michael Fischbach, PhD, a faculty member of the UCSF School of Pharmacy, has developed software to jumpstart that process. This lab bioinformatics program, ClusterFinder, analyzes bacterial genomic data to identify physically clustered groups of genes in a particular genome that together encode enzymes which interact in sequence to produce drug-like small molecules (i.e., biosynthetic gene clusters).

Now, Fischbach is collaborating with scientists at MIT, Harvard University, the Broad Institute, and the Novartis Institutes for BioMedical Research in a planned multi-year project funded by Novartis, the Swiss pharmaceutical giant. The researchers will work to identify, prioritize, synthesize, and test those gene clusters and the molecules they express, along with their chemical variants, as potential drug producers and products.

The goal is to create a synthetic biology pipeline in which gene clusters identified by Fischbach’s lab from a variety of genomic databases—from bacteria found in the environment to the human microbiome—will be effectively transferred (refactored) into production host cells (well understood, readily manipulable unicellular species such as yeast and E. coli) at the MIT-Broad Foundry in Cambridge, Massachusetts, yielding compounds for testing and development by Novartis.

During an 18-month pilot phase, with funding of $2.7 million (about $400,000 for the Fischbach Lab), the research collaboration will develop and demonstrate the pipeline’s core capabilities. This is expected to include refactoring gene clusters found in the human gut microbiome into host organisms in order to chemically map and diversify the structures of the molecules they produce for screening as potential new antibiotics.

As part of the project, the Fischbach Lab will expand upon ClusterFinder, developing an algorithm that predicts the chemical structures of gene cluster products. This will aid the prioritization of clusters to be tested in the pipeline and speed the ensuing detection of their products in the host cells.

At the end of the pilot phase, the researchers expect to have a priority list of target compounds for further analysis and development—those with new and unexplored chemical structures as well as those with potential as disease treatments.

The Fischbach laboratory is based in the Department of Bioengineering and Therapeutic Sciences, a joint department of the UCSF Schools of Pharmacy and Medicine.