title: Assembly and clustering of natural antibiotics guides target identification.
abstract: Antibiotics are essential for numerous medical procedures, including the treatment of bacterial infections, but their widespread use has led to the accumulation of resistance, prompting calls for the discovery of antibacterial agents with new targets. A majority of clinically approved antibacterial scaffolds are derived from microbial natural products, but these valuable molecules are not well annotated or organized, limiting the efficacy of modern informatic analyses. Here, we provide a comprehensive resource defining the targets, chemical origins and families of the natural antibacterial collective through a retrobiosynthetic algorithm. From this we also detail the directed mining of biosynthetic scaffolds and resistance determinants to reveal structures with a high likelihood of having previously unknown modes of action. Implementing this pipeline led to investigations of the telomycin family of natural products from Streptomyces canus, revealing that these bactericidal molecules possess a new antibacterial mode of action dependent on the bacterial phospholipid cardiolipin.
authors.affiliation: Department of Biochemistry &Biomedical Sciences, M.G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.|Department of Chemistry &Chemical Biology, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Chad W
authors.initials: CW
authors.lastname: Johnston
authors.affiliation: Department of Biochemistry &Biomedical Sciences, M.G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.|Department of Chemistry &Chemical Biology, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Michael A
authors.identifier: http://orcid.org/0000-0002-2168-1621
authors.initials: MA
authors.lastname: Skinnider
authors.affiliation: Department of Biochemistry &Biomedical Sciences, M.G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.|Department of Chemistry &Chemical Biology, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Chris A
authors.initials: CA
authors.lastname: Dejong
authors.affiliation: Department of Biochemistry &Biomedical Sciences, M.G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.|Department of Chemistry &Chemical Biology, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Philip N
authors.initials: PN
authors.lastname: Rees
authors.affiliation: Department of Biochemistry &Biomedical Sciences, M.G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.|Department of Chemistry &Chemical Biology, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Chen
authors.affiliation: Department of Biochemistry &Biomedical Sciences, M.G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.|Department of Chemistry &Chemical Biology, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Chelsea G
authors.initials: CG
authors.lastname: Walker
authors.affiliation: Department of Biochemistry &Biomedical Sciences, M.G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Shawn
authors.initials: S
authors.lastname: French
authors.affiliation: Department of Biochemistry &Biomedical Sciences, M.G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Brown
authors.affiliation: Eötvös Loránd University, IVAX Drug Research Institute Ltd., Budapest, Hungary.
authors.forename: János
authors.initials: J
authors.lastname: Bérdy
authors.affiliation: Department of Biochemistry &Biomedical Sciences, M.G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.|Department of Chemistry &Chemical Biology, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Dennis Y
authors.initials: DY
authors.lastname: Liu
authors.affiliation: Department of Biochemistry &Biomedical Sciences, M.G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.|Department of Chemistry &Chemical Biology, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Magarvey
mesh_terms: D000900:Anti-Bacterial Agents / Q000096:biosynthesis / Q000302:isolation & purification / Q000494:pharmacology*; D001688:Biological Products / Q000302:isolation & purification / Q000494:pharmacology*; D053898:Biosynthetic Pathways; D002308:Cardiolipins / Q000096:biosynthesis* / Q000235:genetics; D015169:Colony Count, Microbial; D030541:Databases, Genetic; D024881:Drug Resistance, Bacterial / Q000187:drug effects / Q000235:genetics; D006094:Gram-Positive Bacteria / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D005810:Multigene Family; D010455:Peptides / Q000235:genetics / Q000302:isolation & purification / Q000494:pharmacology*; D013302:Streptomyces / Q000378:metabolism*; D064878:Web Browser
chemical_list: D000900:Anti-Bacterial Agents; D001688:Biological Products; D002308:Cardiolipins; D010455:Peptides; C009392:telomycin
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