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).
Highlights
Pathogenic microorganisms often have the ability to attach to a surface, building a complex matrix where they colonize to form a biofilm
We show that the cahuitamycins are derived from two independent starter unit pathways, one of which is genetically unlinked to the core cluster
The active extracts were further prioritized by setting the inhibition threshold to 50% followed by a dose–response assay, yielding 31 active natural product extract (NPE) (Supplementary Figs 1–2)
Summary
Pathogenic microorganisms often have the ability to attach to a surface, building a complex matrix where they colonize to form a biofilm. This study revealed the extract from Streptomyces gandocaensis to be of particular interest due to its ability to inhibit biofilm formation, but showing a limited effect on A. baumannii growth (Supplementary Figs 1–3).
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