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Author Notes:

Address correspondence to Shonna M. McBride (shonna.mcbride@emory.edu).

Jose M. Suárez and Adrianne N. Edwards contributed equally to this work.

We give special thanks to Linc Sonenshein, the Sonenshein lab members, Andy Camilli, Rita Tamayo, Boris Belitsky, Dervla Isaac, Brandon Anjuwon-Foster, and Charles Moran for helpful suggestions and discussions during the course of this work, Chris O'Brien for help with the lantibiotic consensus prediction, Boris Belitsky for B. subtilis strains and DNA, and Jeremy Boss for use of the Bio-Rad CFX96 real-time PCR detection system.

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Research Funding:

This work was supported by the U.S. National Institutes of Health through research grant AI057637 to Abraham L. Sonenshein, grants DK082156 and DK087763 to S.M.M., a core facility grant (NS047243) to the Tufts University Center for Neuroscience Research, a STEP/HHMI Curriculum Development Fellowship to A.N.E., and a Natalie V. Zucker research grant to S.M.M.

The Clostridium difficilecpr Locus Is Regulated by a Noncontiguous Two-Component System in Response to Type A and B Lantibiotics

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Journal Title:

Journal of Bacteriology

Volume:

Volume 195, Number 11

Publisher:

, Pages 2621-2631

Type of Work:

Article | Final Publisher PDF

Abstract:

The intestinal pathogen Clostridium difficile is known to grow only within the intestines of mammals, yet little is known about how the bacterium subsists in this environment. In the intestine, C. difficile must contend with innate defenses within the host, such as cationic antimicrobial peptides (CAMPs) produced by the host and the indigenous microbiota. In this study, we investigated the mechanism of activation and regulation of the CprABC transporter system, which provides resistance to multiple CAMPs and shows homology to the immunity systems of bacterial antimicrobial peptide producers. The CprABC system proved to be controlled by a noncontiguous two-component system consisting of the CprK sensor kinase and an orphan response regulator (CD3320; CprR). The CprK-CprR regulators were shown to activate cprABCK transcription in a manner similar to that by lantibiotic regulatory systems. Unlike lantibiotic producer regulation, regulation by CprK-CprR was activated by multiple lantibiotics produced by diverse Gram-positive bacteria. We identified a motif within these lantibiotics that is likely required for activation of cpr. Based on the similarities between the Cpr system and lantibiotic systems, we propose that the CprABC transporter and its regulators are relatives of lantibiotic systems that evolved to recognize multiple substrates to defend against toxins made by the intestinal microbiota.

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© 2013, American Society for Microbiology. All Rights Reserved.

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