title: Diaza-anthracene Antibiotics from a Freshwater-Derived Actinomycete with Selective Antibacterial Activity towardMycobacterium tuberculosis.
abstract: Multidrug- and extensively drug-resistant strains ofMycobacterium tuberculosisare resistant to first- and second-line drug regimens and resulted in 210,000 fatalities in 2013. In the current study, we screened a library of aquatic bacterial natural product fractions for their ability to inhibit this pathogen. A fraction from a Lake Michigan bacterium exhibited significant inhibitory activity, from which we characterized novel diazaquinomycins H and J. This antibiotic class displayed an in vitro activity profile similar or superior to clinically used anti-tuberculosis agents and maintained this potency against a panel of drug-resistantM. tuberculosisstrains. Importantly, these are among the only freshwater-derived actinomycete bacterial metabolites described to date. Further in vitro profiling against a broad panel of bacteria indicated that this antibiotic class selectively targetsM. tuberculosis. Additionally, in the case of this pathogen we present evidence counter to previous reports that claim the diazaquinomycins target thymidylate synthase in Gram-positive bacteria. Thus, we establish freshwater environments as potential sources for novel antibiotic leads and present the diazaquinomycins as potent and selective inhibitors ofM. tuberculosis.
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street (MC 781), Room 539, Chicago, Illinois 60612-7231, United States.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Mullowney
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street (MC 781), Room 539, Chicago, Illinois 60612-7231, United States ; Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street (MC 964), Room 412, Chicago, Illinois 60612-7231, United States.
authors.forename: Chang Hwa
authors.initials: CH
authors.lastname: Hwang
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street (MC 781), Room 539, Chicago, Illinois 60612-7231, United States.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Newsome
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street (MC 781), Room 539, Chicago, Illinois 60612-7231, United States.
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Wei
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street (MC 781), Room 539, Chicago, Illinois 60612-7231, United States.
authors.forename: Urszula
authors.initials: U
authors.lastname: Tanouye
authors.affiliation: Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street (MC 964), Room 412, Chicago, Illinois 60612-7231, United States.
authors.forename: Baojie
authors.initials: B
authors.lastname: Wan
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street (MC 781), Room 539, Chicago, Illinois 60612-7231, United States.
authors.forename: Skylar
authors.initials: S
authors.lastname: Carlson
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street (MC 781), Room 539, Chicago, Illinois 60612-7231, United States ; Department of Biopharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street (MC 865), Room 335, Chicago, Illinois 60612-7231, United States.
authors.forename: Nanthida Joy
authors.initials: NJ
authors.lastname: Barranis
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street (MC 781), Room 539, Chicago, Illinois 60612-7231, United States ; Center for Pharmaceutical Biotechnology, College of Pharmacy, University of Illinois at Chicago, Molecular Biology Research Building, 900 South Ashland Avenue (MC 870), Room 3150, Chicago, Illinois 60607-7173, United States.
authors.forename: EoghainínÓ
authors.initials: E
authors.lastname: hAinmhire
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street (MC 781), Room 539, Chicago, Illinois 60612-7231, United States.
authors.forename: Wei-Lun
authors.initials: WL
authors.lastname: Chen
authors.affiliation: Department of Chemistry, University of Washington, Box 351700, Seattle, Washington 98195-1700, United States.
authors.forename: Kalyanaraman
authors.initials: K
authors.lastname: Krishnamoorthy
authors.affiliation: Department of Chemistry, University of Washington, Box 351700, Seattle, Washington 98195-1700, United States.
authors.forename: John
authors.initials: J
authors.lastname: White
authors.affiliation: TB Discovery Research, Infectious Disease Research Institute, 1616 Eastlake Avenue East, Suite 400, Seattle, Washington 98102, United States.
authors.forename: Rachel
authors.initials: R
authors.lastname: Blair
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street (MC 865), Room 335, Chicago, Illinois 60612-7231, United States.
authors.forename: Hyunwoo
authors.initials: H
authors.lastname: Lee
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street (MC 781), Room 539, Chicago, Illinois 60612-7231, United States ; Center for Pharmaceutical Biotechnology, College of Pharmacy, University of Illinois at Chicago, Molecular Biology Research Building, 900 South Ashland Avenue (MC 870), Room 3150, Chicago, Illinois 60607-7173, United States.
authors.forename: Joanna E
authors.initials: JE
authors.lastname: Burdette
authors.affiliation: Department of Chemistry, University of Washington, Box 351700, Seattle, Washington 98195-1700, United States.
authors.forename: Pradipsinh K
authors.initials: PK
authors.lastname: Rathod
authors.affiliation: TB Discovery Research, Infectious Disease Research Institute, 1616 Eastlake Avenue East, Suite 400, Seattle, Washington 98102, United States.
authors.forename: Tanya
authors.initials: T
authors.lastname: Parish
authors.affiliation: Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street (MC 964), Room 412, Chicago, Illinois 60612-7231, United States.
authors.forename: Sanghyun
authors.initials: S
authors.lastname: Cho
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street (MC 781), Room 539, Chicago, Illinois 60612-7231, United States ; Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street (MC 964), Room 412, Chicago, Illinois 60612-7231, United States.
authors.forename: Scott G
authors.initials: SG
authors.lastname: Franzblau
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street (MC 781), Room 539, Chicago, Illinois 60612-7231, United States ; Center for Pharmaceutical Biotechnology, College of Pharmacy, University of Illinois at Chicago, Molecular Biology Research Building, 900 South Ashland Avenue (MC 870), Room 3150, Chicago, Illinois 60607-7173, United States.
authors.forename: Brian T
authors.initials: BT
authors.lastname: Murphy
keywords: Great Lakes; actinobacteria; antibiotic; diazaquinomycin; drug discovery; natural products