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Proc Natl Acad Sci U S A. 2015 Mar 10;112(10):3086-91. doi: 10.1073/pnas.1414272112. Epub 2015 Feb 23.

Thiopeptide antibiotics stimulate biofilm formation in Bacillus subtilis.

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Division of Chemical Biology and Medicinal Chemistry, School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599;
Departments of Pharmacology and Chemistry and Biochemistry, University of California at San Diego, La Jolla, CA 92093; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, La Jolla, CA 92093;
Departments of Biology and Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599; and Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, NC 27599


Bacteria have evolved the ability to produce a wide range of structurally complex natural products historically called "secondary" metabolites. Although some of these compounds have been identified as bacterial communication cues, more frequently natural products are scrutinized for antibiotic activities that are relevant to human health. However, there has been little regard for how these compounds might otherwise impact the physiology of neighboring microbes present in complex communities. Bacillus cereus secretes molecules that activate expression of biofilm genes in Bacillus subtilis. Here, we use imaging mass spectrometry to identify the thiocillins, a group of thiazolyl peptide antibiotics, as biofilm matrix-inducing compounds produced by B. cereus. We found that thiocillin increased the population of matrix-producing B. subtilis cells and that this activity could be abolished by multiple structural alterations. Importantly, a mutation that eliminated thiocillin's antibiotic activity did not affect its ability to induce biofilm gene expression in B. subtilis. We go on to show that biofilm induction appears to be a general phenomenon of multiple structurally diverse thiazolyl peptides and use this activity to confirm the presence of thiazolyl peptide gene clusters in other bacterial species. Our results indicate that the roles of secondary metabolites initially identified as antibiotics may have more complex effects--acting not only as killing agents, but also as specific modulators of microbial cellular phenotypes.


Bacillus cereus; Bacillus subtilis; biofilm formation; thiazolyl antibiotics; thiopeptides

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