Export of a single drug molecule in two transport cycles by a multidrug efflux pump

Nir Fluman, Julia Adler, Susan Rotenberg, Melissa Brown, Eitan Bibi

    Research output: Contribution to journalArticlepeer-review

    23 Citations (Scopus)


    Secondary multidrug transporters use ion concentration gradients to energize the removal from cells of various antibiotics. The Escherichia coli multidrug transporter MdfA exchanges a single proton with a single monovalent cationic drug molecule. This stoichiometry renders the efflux of divalent cationic drugs energetically unfavourable, as it requires exchange with at least two protons. Here we show that surprisingly, MdfA catalyses efflux of divalent cations, provided that they have a unique architecture: the two charged moieties must be separated by a long linker. These drugs are exchanged for two protons despite the apparent inability of MdfA to exchange two protons for a single drug molecule. Our results suggest that these drugs are transported in two consecutive transport cycles, where each cationic moiety is transported as if it were a separate substrate. We propose that secondary transport can adopt a processive-like mode of action, thus expanding the substrate spectrum of multidrug transporters.

    Original languageEnglish
    Article number4615
    Number of pages9
    JournalNature Communications
    Early online date2014
    Publication statusPublished - 8 Aug 2014


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