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

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 () and David H. Sherman ()
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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
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
Abraham Y. Mensah: Life Sciences Institute, University of Michigan
Giselle Tamayo-Castillo: Unidad Estratégica de Bioprospección, Instituto Nacional de Biodiversidad (INBio)
Chuanwu Xi: University of Michigan School of Public Health
David H. Sherman: Life Sciences Institute, University of Michigan

Nature Communications, 2016, vol. 7, issue 1, 1-11

Abstract: 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).

Date: 2016
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DOI: 10.1038/ncomms10710

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