SCIENCE & TECHNOLOGY
MINING THE MICROBIOME Newly discovered natural product is produced OH by HUMAN-HOSTED BACTERIA O A SURVEY of the Human Microbiome
O OH
Project’s genomic database has reN S O H N vealed that the microbes living in O N O and on healthy humans contain S N more than 3,000 sets of instruc- S N O tions for synthesizing small molNH ecules. According to the study, N N S one of those small molecules is N N a newly discovered, naturally ocO curring antibiotic produced by S HN S N N S N S vaginal bacteria (Cell 2014, DOI: 10.1016/j.cell.2014.08.032). N S O O “I’d always thought that O NH NH OH HN drugs are discovered by N NH drug companies, approved HO N NH O S by the Food & Drug AdO HN O S ministration, prescribed by CH3 a physician—and then they Lactocillin LFF571 get to you,” says Michael A. Fischbach, a chemist at the SELF-MEDICATING because of their documentUniversity of California, San ed therapeutic properties. A peptide (left) made Francisco, who led the study. In 2012, pharmaceutiby a human microbe “Human-associated bactecal company Novartis anbears a resemblance ria are mounting an end run nounced it was developing a in form and function to around that process.” drug based on a thiopeptide a semisynthetic drug The newfound antibicalled GE2270A that is procandidate (right). otic, which the research team duced by rare soil microbes dubbed lactocillin, is a member (J. Med. Chem. 2012, DOI: of the thiopeptide family, a class of cyclic 10.1021/jm201685h). The semisynthetic peptides. Scientists studying natural molecule, LFF571, is now being evaluated products have long known that thiopepin Phase II clinical trials as a treatment tides possess antimicrobial properties, so for gastrointestinal infections caused by lactocillin’s activity itself is unsurprising, the bacterium Clostridium difficile. Despite Fischbach says. coming from two completely different What is fascinating, he contends, is the types of bacteria, the genes behind the number of small molecules the microbiproduction of GE2270A and lactocillin are ome is producing and how little scientists remarkably similar, Fischbach says, adding know about them. Researchers have charthat this fact helped his group identify the acterized only a few of the microbiome’s new antibiotic. small-molecule products, largely in one-off studies. THE TEAM WORKED with an algorithm Fischbach and his colleagues introduced that spotted a gene cluster in a vaginal a more systematic approach. By mining microbe that looked like one known to be the microbiome’s genomic data for genes involved in making thiopeptides. This findknown or suspected to guide small-moleing allowed the researchers to then isolate cule synthesis, they revealed which chemithat gene cluster, purify its small-molecule cals microbes are likely making and where: product, and study the thiopeptide’s bioin the gut, on the skin, or in the urogenital logical function. Lactocillin attacked most tract, for instance. The next step would be gram-positive bacteria the team tested to determine the biological function of all it against, with the notable exception of these natural products. The team decided those that are normally present in the vagito investigate thiopeptides first, partially nal microbiome. CEN.ACS.ORG
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The thiopeptide may thus play a role in protecting the vagina against foreign microbes, the researchers report. But because they performed the experiments with cultured bacteria, they don’t yet know whether lactocillin occurs in vivo. Still, their purified antibiotic bears a striking resemblance in both function and H O form to other thiopeptides, including GE2270A and, by extenOH sion, LFF571. “We know that they’re very closely related biosynthetically, but also chemically,” Fischbach says, although he does acknowledge a subtle difference between S the two natural products, lactocillin and GE2270A. “If you’re OH a connoisseur, you would say HN O they belong to two different subclasses of thiopeptides NH because their ring size is N different.” O Some researchers believe S that the Fischbach team’s apOCH3 proach, which weds computational and chemical analyses, could be the key to harnessing the therapeutic potential of human-associated bacteria. “This is a provocative study. I see part of the natural products field going this way in the future, taking more of a bioinformatics approach,” says Matthew J. LaMarche, a senior investigator at Novartis who was involved with the discovery of LFF571. But he adds that it will be some time before such an approach yields novel pharmaceuticals or a concrete understanding of the chemical dialogues within the human microbiome. “We are just at the beginning of the journey,” agrees George M. Weinstock, associate director of microbial genomics at the Jackson Laboratory for Genomic Medicine, a nonprofit research organization. But this study is an exciting and encouraging start, he says. “There will be many more stories like this.” The challenge will be building on this work so that microbiome researchers can address gene clusters in a systematic way and build a pipeline for analyzing their myriad molecular products, Fischbach says. Our bugs are not sitting idle in our bodies, he says, “they’re quite active chemically. I look forward to seeing how we can extend our approach to learn more about the chemistry of perhaps the most important microorganisms on the planet.”— MATT DAVENPORT
