Journal
NATURE MICROBIOLOGY
Volume 1, Issue 1, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/NMICROBIOL.2015.9
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Funding
- University of Florida
- UF DoM Gatorade Fund
- [R01 DK73338]
- [R01DK47700]
- [R01 GM0865700]
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK047700, R01DK073338] Funding Source: NIH RePORTER
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Various forms of cancer have been linked to the carcinogenic activities of microorganisms(1-3). The virulent gene island polyketide synthase (pks) produces the secondary metabolite colibactin, a genotoxic molecule(s) causing double-stranded DNA breaks(4) and enhanced colorectal cancer development(5,6). Colibactin biosynthesis involves a prodrug resistance strategy where an N-terminal prodrug scaffold (precolibactin) is assembled, transported into the periplasm and cleaved to release the mature product(7-10). Here, we show that ClbM, a multidrug and toxic compound extrusion (MATE) transporter, is a key component involved in colibactin activity and transport. Disruption of clbM attenuated pks+ E. coli-induced DNA damage in vitro and significantly decreased the DNA damage response in gnotobiotic Il10(-/-) mice. Colonization experiments performed in mice or zebrafish animal models indicate that clbM is not implicated in E. coli niche establishment. The X-ray structure of ClbM shows a structural motif common to the recently described MATE family. The 12-transmembrane ClbM is characterized as a cation-coupled antiporter, and residues important to the cation-binding site are identified. Our data identify ClbM as a precolibactin transporter and provide the first structure of a MATE transporter with a defined and specific biological function.
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