Antimicrobials Inspired by Nonribosomal Peptide Synthetase Gene Clusters.
Xavier Vila-Farres, John Chu, Daigo Inoyama, Melinda A Ternei, Christophe Lemetre, Louis J Cohen, Wooyoung Cho, Boojala Vijay B Reddy, Henry A Zebroski, Joel S Freundlich, David S Perlin, Sean F Brady
Author Information
Xavier Vila-Farres: Laboratory of Genetically Encoded Small Molecules and ‡Proteomics Resource Center, The Rockefeller University , New York, New York 10065, United States.
John Chu: Laboratory of Genetically Encoded Small Molecules and ‡Proteomics Resource Center, The Rockefeller University , New York, New York 10065, United States. ORCID
Daigo Inoyama: Laboratory of Genetically Encoded Small Molecules and ‡Proteomics Resource Center, The Rockefeller University , New York, New York 10065, United States.
Melinda A Ternei: Laboratory of Genetically Encoded Small Molecules and ‡Proteomics Resource Center, The Rockefeller University , New York, New York 10065, United States.
Christophe Lemetre: Laboratory of Genetically Encoded Small Molecules and ‡Proteomics Resource Center, The Rockefeller University , New York, New York 10065, United States.
Louis J Cohen: Laboratory of Genetically Encoded Small Molecules and ‡Proteomics Resource Center, The Rockefeller University , New York, New York 10065, United States.
Wooyoung Cho: Laboratory of Genetically Encoded Small Molecules and ‡Proteomics Resource Center, The Rockefeller University , New York, New York 10065, United States.
Boojala Vijay B Reddy: Laboratory of Genetically Encoded Small Molecules and ‡Proteomics Resource Center, The Rockefeller University , New York, New York 10065, United States.
Henry A Zebroski: Laboratory of Genetically Encoded Small Molecules and ‡Proteomics Resource Center, The Rockefeller University , New York, New York 10065, United States.
Joel S Freundlich: Laboratory of Genetically Encoded Small Molecules and ‡Proteomics Resource Center, The Rockefeller University , New York, New York 10065, United States.
David S Perlin: Laboratory of Genetically Encoded Small Molecules and ‡Proteomics Resource Center, The Rockefeller University , New York, New York 10065, United States.
Sean F Brady: Laboratory of Genetically Encoded Small Molecules and ‡Proteomics Resource Center, The Rockefeller University , New York, New York 10065, United States.
Bacterial culture broth extracts have been the starting point for the development of numerous therapeutics. However, only a small fraction of bacterial biosynthetic diversity is accessible using this strategy. Here, we apply a discovery approach that bypasses the culturing step entirely by bioinformatically predicting small molecule structures from the primary sequences of the biosynthetic gene clusters. These structures are then chemically synthesized to give synthetic-bioinformatic natural products (syn-BNPs). Using this approach, we screened syn-BNPs inspired by nonribosomal peptide synthetases against microbial pathogens, and discovered an antibiotic for which no resistance could be identified and an antifungal agent with activity against diverse fungal pathogens.
