title: Discovery of cahuitamycins as biofilm inhibitors derived from a convergent biosynthetic pathway.
abstract: Pathogenic microorganisms often have the ability to attach to a surface, building a complex matrix where they colonize to form a biofilm. This cellular superstructure can display increased resistance to antibiotics and cause serious, persistent health problems in humans. Here we describe a high-throughput in vitro screen to identify inhibitors of Acinetobacter baumannii biofilms using a library of natural product extracts derived from marine microbes. Analysis of extracts derived from Streptomyces gandocaensis results in the discovery of three peptidic metabolites (cahuitamycins A-C), with cahuitamycin C being the most effective inhibitor (IC50=14.5 μM). Biosynthesis of cahuitamycin C proceeds via a convergent biosynthetic pathway, with one of the steps apparently being catalysed by an unlinked gene encoding a 6-methylsalicylate synthase. Efforts to assess starter unit diversification through selective mutasynthesis lead to production of unnatural analogues cahuitamycins D and E of increased potency (IC50=8.4 and 10.5 μM).
authors.affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Sung Ryeol
authors.initials: SR
authors.lastname: Park
authors.affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Ashootosh
authors.identifier: http://orcid.org/0000-0003-2297-8088
authors.initials: A
authors.lastname: Tripathi
authors.affiliation: Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, Michigan 48109, USA.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Wu
authors.affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Schultz
authors.affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Isaiah
authors.initials: I
authors.lastname: Yim
authors.affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: McQuade
authors.affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Fengan
authors.initials: F
authors.lastname: Yu
authors.affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Carl-Johan
authors.initials: CJ
authors.lastname: Arevang
authors.affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Abraham Y
authors.initials: AY
authors.lastname: Mensah
authors.affiliation: Unidad Estratégica de Bioprospección, Instituto Nacional de Biodiversidad (INBio), Santo Domingo de Heredia 223100, Costa Rica.|CIPRONA, Escuela de Química, Universidad de Costa Rica, 2060 San José, Costa Rica.
authors.forename: Giselle
authors.initials: G
authors.lastname: Tamayo-Castillo
authors.affiliation: Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, Michigan 48109, USA.
authors.forename: Chuanwu
authors.initials: C
authors.lastname: Xi
authors.affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA.|Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA.|Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA.|Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: Sherman
mesh_terms: D040981:Acinetobacter baumannii / Q000187:drug effects* / Q000502:physiology; D000900:Anti-Bacterial Agents / Q000096:biosynthesis / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000096:biosynthesis / Q000494:pharmacology*; D018441:Biofilms / Q000187:drug effects*; D053898:Biosynthetic Pathways; D057166:High-Throughput Screening Assays; D009842:Oligopeptides / Q000096:biosynthesis / Q000494:pharmacology*; D013302:Streptomyces
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D009842:Oligopeptides; C000608617:cahuitamycin A protein, Streptomyces gandocaensis; C000608618:cahuitamycin B protein, Streptomyces gandocaensis; C000608619:cahuitamycin C protein, Streptomyces gandocaensis