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Discovery of cahuitamycins as biofilm inhibitors derived from a convergent biosynthetic pathway

Author

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  • Sung Ryeol Park

    (Life Sciences Institute, University of Michigan)

  • Ashootosh Tripathi

    (Life Sciences Institute, University of Michigan)

  • Jianfeng Wu

    (University of Michigan School of Public Health)

  • Pamela J. Schultz

    (Life Sciences Institute, University of Michigan)

  • Isaiah Yim

    (Life Sciences Institute, University of Michigan
    Present Address: National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702, USA)

  • Thomas J. McQuade

    (Life Sciences Institute, University of Michigan)

  • Fengan Yu

    (Life Sciences Institute, University of Michigan)

  • Carl-Johan Arevang

    (Life Sciences Institute, University of Michigan
    Present Address: Karolinska Institutet Science Park, Retzius vag 8, 17165 Solna, Sweden)

  • Abraham Y. Mensah

    (Life Sciences Institute, University of Michigan
    Present Address: Department of Pharmacognosy, College of Health Sciences, Kwame Nkrumah University of Science & Technology, Kumasi, Ghana)

  • Giselle Tamayo-Castillo

    (Unidad Estratégica de Bioprospección, Instituto Nacional de Biodiversidad (INBio)
    CIPRONA, Escuela de Química, Universidad de Costa Rica)

  • Chuanwu Xi

    (University of Michigan School of Public Health)

  • David H. Sherman

    (Life Sciences Institute, University of Michigan
    University of Michigan
    University of Michigan
    University of Michigan)

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).

Suggested Citation

  • Sung Ryeol Park & Ashootosh Tripathi & Jianfeng Wu & Pamela J. Schultz & Isaiah Yim & Thomas J. McQuade & Fengan Yu & Carl-Johan Arevang & Abraham Y. Mensah & Giselle Tamayo-Castillo & Chuanwu Xi & Da, 2016. "Discovery of cahuitamycins as biofilm inhibitors derived from a convergent biosynthetic pathway," Nature Communications, Nature, vol. 7(1), pages 1-11, April.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms10710
    DOI: 10.1038/ncomms10710
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