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Small molecules encoded by biosynthetic gene clusters are widely used in the clinic and constitute much of the chemical language of interspecies interactions. In a recent study, researchers used a systematic approach to identify more than 3,000 small-molecule biosynthetic gene clusters in the genomes of human-associated bacteria. As reported in Cell, they discovered that biosynthetic gene clusters for thiopeptides—a class of antibiotics—are widely distributed in the genomes of the human microbiota.

“This study shows for the first time that our microbiota—the good microbes that live with humans—produce drug-like molecules to protect us from pathogens,” said lead study author Mohamed Donia of the University of California, San Francisco (UCSF). “For a long time, scientists used to go to remote and exotic places to find bacteria that produce novel chemical entities with drug-like properties. Who knew we could find similar ones in our own bodies?”

Donia and his collaborators used an algorithm they recently developed to systematically analyze about 2,400 reference genomes of the human microbiota from various body sites. They detected more than 14,000 biosynthetic gene clusters for a broad range of small-molecule classes. Reasoning that the products of these gene clusters are most likely to mediate conserved microbe-host and microbe-microbe interactions, they set out to identify the subset of gene clusters commonly found in healthy individuals by analyzing 752 metagenomic samples from the National Institutes of Health Human Microbiome Project.

Remarkably, nearly all of these gene clusters had never before been studied or even described, illustrating how little is known about their small-molecule products. “We need to study every single one of these molecules and understand what they are doing,” Donia said. “We have published the list of the small molecule-encoding genes that we identified, and we are reaching out to the scientific community to help us characterize them.”

Thiopeptides are perhaps the most interesting of these molecules because they have potent antibacterial activity against Gram-positive species. Currently, one semisynthetic member of this class is undergoing clinical trials for treating bacterial infections. But according to the authors, no thiopeptide biosynthetic gene cluster or small-molecule product from the human microbiome had ever been experimentally characterized. Surprisingly, their analysis revealed thiopeptide-like biosynthetic gene clusters in isolates from every human body site.

Donia and his collaborators went on to purify and solve the structure of a thiopeptide named lactocillin, which showed potent antibacterial activity against a range of Gram-positive vaginal pathogens. By analyzing human metatranscriptomic sequencing data, they showed that lactocillin and other thiopeptide biosynthetic gene clusters were expressed in vivo, suggesting a potential role in mediating microbe-microbe interactions.

Source: www.biotechniques.com

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