Genetically Encoded Small Molecules Mining Metagenomes for Drugs
Screen soils for molecules

Genetically Encoded Small Molecules
Mining Metagenomes for Drugs

Human microbiome
Digging soil sample

We screen soils for molecules

Metagenomics soil screening for genetically encoded small molecules has allowed for the successful characterization of several new molecules and classes of molecules of high therapeutic importance. This is becoming increasingly critical as we have entered in an era deemed “post-antibiotics”.

Extracts of bacterial culture broths have been the starting point for the development of numerous therapeutics. However, only a very small fraction of bacterial biosynthetic diversity is accessible through this strategy. We have developed a discovery approach that bypasses the culturing step entirely. This approach starts with bioinformatically predicting small molecule structures from the primary sequences of biosynthetic gene clusters. These structures are then chemically synthesized to givet synthetic-bioinformatic natural products (syn-BNPs). Syn-BNPs are not meant to be exact replica of natural products; instead they are close structural mimics to facilitate the discvoery of bioactive molecular scaffolds. Using this approach, we produced syn-BNPs inspired by nonribosomal peptide synthetases (NRPS) found in the human and soil microbiomes and screened them against microbial pathogens. This approach has led to the discovery of new antibiotics against MRSA and multidrug-resistant A. baumannii, as well as a new antifungal agent against C. albicans. As DNA sequencing technology and prediction algorithms continue to improve, the syn-BNP approach is poised to uncover even more bioactive molecules in years to come.

Learn More Close
Digging soil sample

Human microbiome

Decoding the language that commensal bacteria use to communicate with the human host can be accomplished by discovering the molecules that bacteria can construct and secrete. We utilize multi-faceted analytical chemistry to identify these secreted molecules and followup with targeted biological studies to elucidate these molecular interactions.

Extracts of bacterial culture broths have been the starting point for the development of numerous therapeutics. However, only a very small fraction of bacterial biosynthetic diversity is accessible through this strategy. We have developed a discovery approach that bypasses the culturing step entirely. This approach starts with bioinformatically predicting small molecule structures from the primary sequences of biosynthetic gene clusters. These structures are then chemically synthesized to give synthetic-bioinformatic natural products (syn-BNPs). Syn-BNPs are not meant to be exact replica of natural products; instead they are close structural mimics to facilitate the discvoery of bioactive molecular scaffolds. Using this approach, we produced syn-BNPs inspired by nonribosomal peptide synthetases (NRPS) found in the human and soil microbiomes and screened them against microbial pathogens. This approach has led to the discovery of new antibiotics against MRSA and multidrug-resistant A. baumannii, as well as a new antifungal agent against C. albicans. As DNA sequencing technology and prediction algorithms continue to improve, the syn-BNP approach is poised to uncover even more bioactive molecules in years to come.

Learn More Close

Publications

  • Accessing Bioactive Natural Products from the Human Microbiome. 06-2018. Milshteyn A, Colosimo DA, Brady SF. Cell Host & Microbe.
  • Culture-independent discovery of the malacidins as calcium-dependent antibiotics with activity against multidrug-resistant Gram-positive pathogens. 02-2018. Hover BM, Kim SH, Katz M, Charlop-Powers Z, Owen JG, Ternei MA, Maniko J, Estrela AB, Molina H, Park S, Perlin DS & Brady SF. Nature Microbiology.
  • Human Microbiome Inspired Antibiotics with Improved beta-Lactam Synergy against MDR Staphylococcus aureus. 01-2018. Chu J, Vila-Farres X, Inoyama D, Gallardo-Macias R, Jankowski M, Satish S, Freundlich JS, Brady SF. ACS Infectious Diseases.
  • Identification of the Colicin V Bacteriocin Gene Cluster by Functional Screening of a Human Microbiome Metagenomic Library . 01-2018. Cohen LJ, Han S, Huang YH, Brady SF. ACS Infectious Diseases.
  • An Optimized Synthetic-Bioinformatic Natural Product Antibiotic Sterilizes Multidrug-Resistant &ITAcinetobacter baumannii&IT-Infected Wounds . 01-2018. Vila-Farres X, Chu J, Ternei MA, Lemetre C, Park S, Perlin DS, Brady SF. Msphere.
  • Commensal bacteria make GPCR ligands that mimic human signalling molecules. 09-2017. Cohen LJ, Esterhazy D, Kim SH, Lemetre C, Aguilar RR, Gordon EA, Pickard AJ, Cross JR, Emiliano AB, Han SM, Chu J, Vila-Farres X, Kaplitt J, Rogoz A, Calle PY, Hunter C, Bitok JK, Brady SF. Nature.
  • Bacterial natural product biosynthetic domain composition in soil correlates with changes in latitude on a continent-wide scale . 08-2017. Lemetre C, Maniko J, Charlop-Powers Z, Sparrow B, Lowe AJ, Brady SF. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES.
  • Antimicrobials Inspired by Nonribosomal Peptide Synthetase Gene Clusters. 02-2017. Vila-Farres X, Chu J, Inoyama D, Ternei MA, Lemetre C, Cohen LJ, Cho W, Reddy BVB, Zebroski HA, Freundlich JS, Perlin DS, Brady SF. Journal of the American Chemical Society.
  • Biotechnological potential of Actinobacteria from Canadian and Azorean volcanic caves. 01-2017. Riquelme C, Dapkevicius M, Miller AZ, Charlop-Powers Z, Brady SF, Mason C, Cheeptham N. Applied Microbiology and Biotechnology.
  • Urban park soil microbiomes are a rich reservoir of natural product biosynthetic diversity. 12-2016. Charlop-Powers Z, Pregitzer CC, Lemetre C, Ternei MA, Maniko J, Hover BM, Calle PY, McGuire KL, Garbarino J, Forgione HM, Charlop-Powers S, Brady SF PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES.

Learn More

News

  • Feb 14, 2018Malacidins: a new class of antibiotics isolated from dirt

    Bradley Hover of the Brady lab, recently reported in a Nature Microbiology article the discovery of a new class of calcium-dependent antibiotics isolated from soil samples. This new class, malacidins is reported to display activity against multidrug-resistant pathogens. The breakthrough discovery has been highlighted in Nature and was also feat... continue reading

  • Jan 16, 2018Wired magazine article

    The Brady lab as well as drugsfromdirt are being featured in this January 2018 Wired magazine edition. You can read all about it here. Have a look! The DFD Team continue reading

  • Dec 6, 2017Enrolling interested teachers

    The DFD program is interested to work with a school teacher or a college professor to develop a curriculum around this Citizen Science project. If you are a school teacher and interested in this, please reach out to us at drugsfromdirt@gmail.com. We are looking forward to be working with you on this. A summer internship is available. The DFD team continue reading

  • Nov 29, 2017We're back!

    We are delighted to announce that the new version of the Drugs From Dirt website and program are now up and running. A new team has taken over the project. As the program resumes, and the analysis is conducted we will release the data as it comes. Stay tuned! The DFD Team continue reading

  • Sep 15, 2017Bacterial natural product biosynthetic domain composition in soil correlates with changes in latitude on a continent-wide scale

    The Rockefeller University laboratory of genetically encoded small molecules led by Dr. Sean Brady succesfully published another study in the prestigious scientific journal PNAS. The results of this study were also featured in an article by Andrea Du Toit in Nature Microbiology Reviews as a research highlight, as well as in the November 2017 TE... continue reading

  • Oct 20, 2016Urban park soil microbiomes are a rich reservoir of natural product biosynthetic diversity

    A new research article by Dr. Sean Brady and his team at the Rockefeller University laboratory of genetically encoded small molecules has been published in the prestigious scientific journal PNAS focusing on the biosynthetic diversity of bacterial natural products across different urban parks in the New York City area. The study suggests that de... continue reading

More News