Toxin import through the antibiotic efflux channel TolC

Nicholas G. Housden, Melissa N. Webby, Edward D. Lowe, Tarick J. El-Baba, Renata Kaminska, Christina Redfield, Carol V. Robinson and Colin Kleanthous ()
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Nicholas G. Housden: University of Oxford
Melissa N. Webby: University of Oxford
Edward D. Lowe: University of Oxford
Tarick J. El-Baba: University of Oxford
Renata Kaminska: University of Oxford
Christina Redfield: University of Oxford
Carol V. Robinson: University of Oxford
Colin Kleanthous: University of Oxford

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: Abstract Bacteria often secrete diffusible protein toxins (bacteriocins) to kill bystander cells during interbacterial competition. Here, we use biochemical, biophysical and structural analyses to show how a bacteriocin exploits TolC, a major outer-membrane antibiotic efflux channel in Gram-negative bacteria, to transport itself across the outer membrane of target cells. Klebicin C (KlebC), a rRNase toxin produced by Klebsiella pneumoniae, binds TolC of a related species (K. quasipneumoniae) with high affinity through an N-terminal, elongated helical hairpin domain common amongst bacteriocins. The KlebC helical hairpin opens like a switchblade to bind TolC. A cryo-EM structure of this partially translocated state, at 3.1 Å resolution, reveals that KlebC associates along the length of the TolC channel. Thereafter, the unstructured N-terminus of KlebC protrudes beyond the TolC iris, presenting a TonB-box sequence to the periplasm. Association with proton-motive force-linked TonB in the inner membrane drives toxin import through the channel. Finally, we demonstrate that KlebC binding to TolC blocks drug efflux from bacteria. Our results indicate that TolC, in addition to its known role in antibiotic export, can function as a protein import channel for bacteriocins.

Date: 2021
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DOI: 10.1038/s41467-021-24930-y

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