Researchers at the University of California, San Diego say they have developed a new genetic platform that allows efficient production of naturally occurring molecules. They then used it to produce a novel antibiotic compound, they add.
The UC-San Diego team believes their study (“Direct cloning and refactoring of a silent lipopeptide biosynthetic gene cluster yields the antibiotic taromycin A”), which is published in the Proceedings of the National Academy of Sciences, may open new avenues for natural product discoveries and drug development.
According to lead investigator Bradley S. Moore, Ph.D., of the Scripps Institution of Oceanography and Skaggs School of Pharmacy and Pharmaceutical Sciences at UC-San Diego, the findings demonstrate a “plug-and-play” technique to trigger previously unknown biosynthetic pathways and identify natural product drug candidates.
“In my opinion, the new synthetic biology technology we developed–which resulted in the discovery of a new antibiotic from a marine bacterium–is just the tip of the iceberg in terms of our ability to modernize the natural product drug discovery platform,” said Dr. Moore.
The ocean, covering 70% of the earth's surface, is a rich source of new microbial diversity for the discovery of new natural products effective as drugs for treating infections, cancer and other important medical conditions, explained Dr. Moore. Most natural antibiotics are complex molecules that are assembled by a special group of enzymes genetically encoded in the microbe's chromosome, he noted, adding that it often proves difficult to grow the newly discovered ocean bacteria in the laboratory, or to get them to produce their full repertoire of natural products.
He and his colleagues harvested a set of genes predicted to encode a natural product from ocean bacteria, then used their synthetic biology technology to identify and test a totally new antibiotic (taromycin A), which found to be effective in fighting methicillin-resistant Staphylococcus aureus.
“With this method, which involves regulatory gene remodeling, we successfully expressed a 67 kb nonribosomal peptide synthetase biosynthetic gene cluster from the marine actinomycete Saccharomonospora sp. CNQ-490 and produced the dichlorinated lipopeptide antibiotic taromycin A in the model expression host Streptomyces coelicolor,” wrote the investigators. “The taromycin gene cluster (tar) is highly similar to the clinically approved antibiotic daptomycin from Streptomyces roseosporus, but has notable structural differences in three amino acid residues and the lipid side chain.”
“The technique has the potential to unlock the drug discovery potential of countless new and mysterious microbes,” said co-investigator Victor Nizet, M.D., professor of pediatrics and pharmacy at UC-San Diego.