title: An Engineered Allele of afsQ1 Facilitates the Discovery and Investigation of Cryptic Natural Products.
abstract: New approaches to antimicrobial discovery are needed to address the growing threat of antibiotic resistance. The Streptomyces genus, a proven source of antibiotics, is recognized as having a large reservoir of untapped secondary metabolic genes, many of which are likely to produce uncharacterized compounds. However, most of these compounds are currently inaccessible, as they are not expressed under standard laboratory conditions. Here, we present a novel methodology for activating these "cryptic" metabolites by heterologously expressing a constitutively active pleiotropic regulator. By screening wild Streptomyces isolates, we identified the antibiotic siamycin-I, a lasso peptide that we show is active against multidrug pathogens. We further revealed that siamycin-I interferes with cell wall integrity via lipid II. This new technology has the potential to be broadly applied for use in the discovery of additional "cryptic" metabolites.
authors.affiliation: Department of Biochemistry, University of Toronto , MaRS Centre - West Tower, 661 University Avenue, Toronto, Ontario M5G 1M1, Canada.
authors.forename: Martin
authors.identifier: 0000-0001-6747-660X
authors.initials: M
authors.lastname: Daniel-Ivad
authors.affiliation: Department of Biochemistry, University of Toronto , MaRS Centre - West Tower, 661 University Avenue, Toronto, Ontario M5G 1M1, Canada.
authors.forename: Nabeela
authors.initials: N
authors.lastname: Hameed
authors.affiliation: Department of Biochemistry, University of Toronto , MaRS Centre - West Tower, 661 University Avenue, Toronto, Ontario M5G 1M1, Canada.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Tan
authors.affiliation: Department of Biochemistry, University of Toronto , MaRS Centre - West Tower, 661 University Avenue, Toronto, Ontario M5G 1M1, Canada.
authors.forename: Rachna
authors.initials: R
authors.lastname: Dhanjal
authors.affiliation: Department of Biochemistry, University of Toronto , MaRS Centre - West Tower, 661 University Avenue, Toronto, Ontario M5G 1M1, Canada.
authors.forename: Daniel
authors.initials: D
authors.lastname: Socko
authors.affiliation: Department of Biology, McMaster University , 1280 Main Street W, Hamilton, Ontario L8S 4K1, Canada.|Michael G. DeGroote Institute for Infectious Disease Research, McMaster University , 1280 Main St W., Hamilton, Ontario L8S 4K1, Canada.
authors.forename: Patricia
authors.initials: P
authors.lastname: Pak
authors.affiliation: Department of Biochemistry, University of Toronto , MaRS Centre - West Tower, 661 University Avenue, Toronto, Ontario M5G 1M1, Canada.
authors.forename: Tomas
authors.initials: T
authors.lastname: Gverzdys
authors.affiliation: Department of Biology, McMaster University , 1280 Main Street W, Hamilton, Ontario L8S 4K1, Canada.|Michael G. DeGroote Institute for Infectious Disease Research, McMaster University , 1280 Main St W., Hamilton, Ontario L8S 4K1, Canada.
authors.forename: Marie A
authors.initials: MA
authors.lastname: Elliot
authors.affiliation: Department of Biochemistry, University of Toronto , MaRS Centre - West Tower, 661 University Avenue, Toronto, Ontario M5G 1M1, Canada.
authors.forename: Justin R
authors.identifier: 0000-0001-7909-1803
authors.initials: JR
authors.lastname: Nodwell
mesh_terms: D000483:Alleles; D001688:Biological Products / Q000737:chemistry*; D055808:Drug Discovery; D005798:Genes, Bacterial; D055432:Metabolomics; D013302:Streptomyces / Q000235:genetics
chemical_list: D001688:Biological Products