title: Discovery of MRSA active antibiotics using primary sequence from the human microbiome.
abstract: Here we present a natural product discovery approach, whereby structures are bioinformatically predicted from primary sequence and produced by chemical synthesis (synthetic-bioinformatic natural products, syn-BNPs), circumventing the need for bacterial culture and gene expression. When we applied the approach to nonribosomal peptide synthetase gene clusters from human-associated bacteria, we identified the humimycins. These antibiotics inhibit lipid II flippase and potentiate β-lactam activity against methicillin-resistant Staphylococcus aureus in mice, potentially providing a new treatment regimen.
authors.affiliation: Laboratory of Genetically Encoded Small Molecules, The Rockefeller University, New York, New York, USA.
authors.forename: John
authors.initials: J
authors.lastname: Chu
authors.affiliation: Laboratory of Genetically Encoded Small Molecules, The Rockefeller University, New York, New York, USA.
authors.forename: Xavier
authors.initials: X
authors.lastname: Vila-Farres
authors.affiliation: Department of Pharmacology, Physiology, and Neuroscience, Rutgers University-New Jersey Medical School, Newark, New Jersey, USA.
authors.forename: Daigo
authors.initials: D
authors.lastname: Inoyama
authors.affiliation: Laboratory of Genetically Encoded Small Molecules, The Rockefeller University, New York, New York, USA.
authors.forename: Melinda
authors.initials: M
authors.lastname: Ternei
authors.affiliation: Laboratory of Genetically Encoded Small Molecules, The Rockefeller University, New York, New York, USA.
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Cohen
authors.affiliation: Laboratory of Genetically Encoded Small Molecules, The Rockefeller University, New York, New York, USA.
authors.forename: Emma A
authors.initials: EA
authors.lastname: Gordon
authors.affiliation: Laboratory of Genetically Encoded Small Molecules, The Rockefeller University, New York, New York, USA.
authors.forename: Boojala Vijay B
authors.initials: BV
authors.lastname: Reddy
authors.affiliation: Laboratory of Genetically Encoded Small Molecules, The Rockefeller University, New York, New York, USA.
authors.forename: Zachary
authors.identifier: http://orcid.org/0000-0001-8816-4680
authors.initials: Z
authors.lastname: Charlop-Powers
authors.affiliation: Proteomics Resource Center, The Rockefeller University, New York, New York, USA.
authors.forename: Henry A
authors.initials: HA
authors.lastname: Zebroski
authors.affiliation: Department of Pharmacology, Physiology, and Neuroscience, Rutgers University-New Jersey Medical School, Newark, New Jersey, USA.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Gallardo-Macias
authors.affiliation: Department of Pharmacology, Physiology, and Neuroscience, Rutgers University-New Jersey Medical School, Newark, New Jersey, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Jaskowski
authors.affiliation: Department of Pharmacology, Physiology, and Neuroscience, Rutgers University-New Jersey Medical School, Newark, New Jersey, USA.
authors.forename: Shruthi
authors.initials: S
authors.lastname: Satish
authors.affiliation: Public Health Research Institute, Rutgers University-New Jersey Medical School, Newark, New Jersey, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Park
authors.affiliation: Public Health Research Institute, Rutgers University-New Jersey Medical School, Newark, New Jersey, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Perlin
authors.affiliation: Department of Pharmacology, Physiology, and Neuroscience, Rutgers University-New Jersey Medical School, Newark, New Jersey, USA.
authors.forename: Joel S
authors.initials: JS
authors.lastname: Freundlich
authors.affiliation: Laboratory of Genetically Encoded Small Molecules, The Rockefeller University, New York, New York, USA.
authors.forename: Sean F
authors.initials: SF
authors.lastname: Brady
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D001688:Biological Products / Q000138:chemical synthesis / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D055666:Lipopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000201:enzymology; D008826:Microbial Sensitivity Tests; D064307:Microbiota / Q000235:genetics*; D008968:Molecular Conformation; D010453:Peptide Synthases / Q000235:genetics; D047090:beta-Lactams / Q000819:agonists / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D001688:Biological Products; D055666:Lipopeptides; D047090:beta-Lactams; C000618317:humimycin A; C000618318:humimycin B; D010453:Peptide Synthases; C104385:non-ribosomal peptide synthase