title: Antimicrobials Inspired by Nonribosomal Peptide Synthetase Gene Clusters.
abstract: 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.
authors.affiliation: Laboratory of Genetically Encoded Small Molecules and ‡Proteomics Resource Center, The Rockefeller University , New York, New York 10065, United States.|Department of Pharmacology, Physiology, and Neuroscience and ∥Public Health Research Institute, Rutgers University , Newark, New Jersey 07103, United States.
authors.forename: Xavier
authors.initials: X
authors.lastname: Vila-Farres
authors.affiliation: Laboratory of Genetically Encoded Small Molecules and ‡Proteomics Resource Center, The Rockefeller University , New York, New York 10065, United States.|Department of Pharmacology, Physiology, and Neuroscience and ∥Public Health Research Institute, Rutgers University , Newark, New Jersey 07103, United States.
authors.forename: John
authors.identifier: 0000-0002-7033-7229
authors.initials: J
authors.lastname: Chu
authors.affiliation: Laboratory of Genetically Encoded Small Molecules and ‡Proteomics Resource Center, The Rockefeller University , New York, New York 10065, United States.|Department of Pharmacology, Physiology, and Neuroscience and ∥Public Health Research Institute, Rutgers University , Newark, New Jersey 07103, United States.
authors.forename: Daigo
authors.initials: D
authors.lastname: Inoyama
authors.affiliation: Laboratory of Genetically Encoded Small Molecules and ‡Proteomics Resource Center, The Rockefeller University , New York, New York 10065, United States.|Department of Pharmacology, Physiology, and Neuroscience and ∥Public Health Research Institute, Rutgers University , Newark, New Jersey 07103, United States.
authors.forename: Melinda A
authors.initials: MA
authors.lastname: Ternei
authors.affiliation: Laboratory of Genetically Encoded Small Molecules and ‡Proteomics Resource Center, The Rockefeller University , New York, New York 10065, United States.|Department of Pharmacology, Physiology, and Neuroscience and ∥Public Health Research Institute, Rutgers University , Newark, New Jersey 07103, United States.
authors.forename: Christophe
authors.initials: C
authors.lastname: Lemetre
authors.affiliation: Laboratory of Genetically Encoded Small Molecules and ‡Proteomics Resource Center, The Rockefeller University , New York, New York 10065, United States.|Department of Pharmacology, Physiology, and Neuroscience and ∥Public Health Research Institute, Rutgers University , Newark, New Jersey 07103, United States.
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Cohen
authors.affiliation: Laboratory of Genetically Encoded Small Molecules and ‡Proteomics Resource Center, The Rockefeller University , New York, New York 10065, United States.|Department of Pharmacology, Physiology, and Neuroscience and ∥Public Health Research Institute, Rutgers University , Newark, New Jersey 07103, United States.
authors.forename: Wooyoung
authors.initials: W
authors.lastname: Cho
authors.affiliation: Laboratory of Genetically Encoded Small Molecules and ‡Proteomics Resource Center, The Rockefeller University , New York, New York 10065, United States.|Department of Pharmacology, Physiology, and Neuroscience and ∥Public Health Research Institute, Rutgers University , Newark, New Jersey 07103, United States.
authors.forename: Boojala Vijay B
authors.initials: BV
authors.lastname: Reddy
authors.affiliation: Laboratory of Genetically Encoded Small Molecules and ‡Proteomics Resource Center, The Rockefeller University , New York, New York 10065, United States.|Department of Pharmacology, Physiology, and Neuroscience and ∥Public Health Research Institute, Rutgers University , Newark, New Jersey 07103, United States.
authors.forename: Henry A
authors.initials: HA
authors.lastname: Zebroski
authors.affiliation: Laboratory of Genetically Encoded Small Molecules and ‡Proteomics Resource Center, The Rockefeller University , New York, New York 10065, United States.|Department of Pharmacology, Physiology, and Neuroscience and ∥Public Health Research Institute, Rutgers University , Newark, New Jersey 07103, United States.
authors.forename: Joel S
authors.initials: JS
authors.lastname: Freundlich
authors.affiliation: Laboratory of Genetically Encoded Small Molecules and ‡Proteomics Resource Center, The Rockefeller University , New York, New York 10065, United States.|Department of Pharmacology, Physiology, and Neuroscience and ∥Public Health Research Institute, Rutgers University , Newark, New Jersey 07103, United States.
authors.forename: David S
authors.initials: DS
authors.lastname: Perlin
authors.affiliation: Laboratory of Genetically Encoded Small Molecules and ‡Proteomics Resource Center, The Rockefeller University , New York, New York 10065, United States.|Department of Pharmacology, Physiology, and Neuroscience and ∥Public Health Research Institute, Rutgers University , Newark, New Jersey 07103, United States.
authors.forename: Sean F
authors.initials: SF
authors.lastname: Brady
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000935:Antifungal Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects*; D001688:Biological Products / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D019295:Computational Biology; D005658:Fungi / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D005810:Multigene Family; D010453:Peptide Synthases / Q000235:genetics* / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D001688:Biological Products; D010453:Peptide Synthases; C104385:non-ribosomal peptide synthase