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Research Article

Thiopeptide antibiotics stimulate biofilm formation in Bacillus subtilis

Rachel Bleich, Jeramie D. Watrous, Pieter C. Dorrestein, Albert A. Bowers, and Elizabeth A. Shank
  1. aDivision of Chemical Biology and Medicinal Chemistry, School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599;
  2. Departments of bPharmacology and
  3. cChemistry and Biochemistry, University of California at San Diego, La Jolla, CA 92093;
  4. dSkaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, La Jolla, CA 92093;
  5. Departments of eBiology and
  6. fMicrobiology and Immunology, University of North Carolina, Chapel Hill, NC 27599; and
  7. gCurriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, NC 27599

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PNAS first published February 23, 2015; https://doi.org/10.1073/pnas.1414272112
Rachel Bleich
aDivision of Chemical Biology and Medicinal Chemistry, School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599;
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Jeramie D. Watrous
Departments of bPharmacology and
cChemistry and Biochemistry, University of California at San Diego, La Jolla, CA 92093;
dSkaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, La Jolla, CA 92093;
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Pieter C. Dorrestein
Departments of bPharmacology and
cChemistry and Biochemistry, University of California at San Diego, La Jolla, CA 92093;
dSkaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, La Jolla, CA 92093;
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Albert A. Bowers
aDivision of Chemical Biology and Medicinal Chemistry, School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599;
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Elizabeth A. Shank
Departments of eBiology and
fMicrobiology and Immunology, University of North Carolina, Chapel Hill, NC 27599; and
gCurriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, NC 27599
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  • For correspondence: eshank@unc.edu
  1. Edited by Jerrold Meinwald, Cornell University, Ithaca, NY, and approved January 29, 2015 (received for review July 28, 2014)

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Significance

Thiazolyl peptides are known antibiotics produced by diverse bacterial taxa. It has been believed that antibiotics are deployed by bacteria as weapons, providing them with an evolutionary advantage over other microbes. We show here that these weapons can also act as chemical tools that elicit biofilm production in the model bacterium Bacillus subtilis. Importantly, the biofilm-inducing (and therefore signaling) properties of these compounds are independent of their killing activity. We go on to use this biofilm-inducing activity to identify and confirm the presence of thiazolyl peptide gene clusters in other bacteria. These results indicate that thiazolyl peptides, and potentially other antibiotics, have the ability to alter bacterial behavior in ways important both to the environment and to human health.

Abstract

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.

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

Footnotes

  • ↵1To whom correspondence should be addressed. Email: eshank{at}unc.edu.
  • Author contributions: A.A.B. and E.A.S. designed research; R.B. and E.A.S. performed research; J.D.W. and P.C.D. contributed new reagents/analytic tools; R.B. and E.A.S. analyzed data; and R.B., A.A.B., and E.A.S. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1414272112/-/DCSupplemental.

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Thiopeptides and biofilm formation
Rachel Bleich, Jeramie D. Watrous, Pieter C. Dorrestein, Albert A. Bowers, Elizabeth A. Shank
Proceedings of the National Academy of Sciences Feb 2015, 201414272; DOI: 10.1073/pnas.1414272112

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Thiopeptides and biofilm formation
Rachel Bleich, Jeramie D. Watrous, Pieter C. Dorrestein, Albert A. Bowers, Elizabeth A. Shank
Proceedings of the National Academy of Sciences Feb 2015, 201414272; DOI: 10.1073/pnas.1414272112
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