2.A.1.2.19
The multidrug (chloramphenicol, tetracycline, norfloxacin, doxorubicin, trimethoprim, acriflavin, ethidium bromide, tetraphenylphosphonium, TPP, benzalkonium, ciprofloxacin, thiamphenicol, IPTG) resistance exporter, MdfA (catalyzes both electrogenic and electroneutral transport) (Adler and Bibi, 2004). Can function as a Na⁺ (K⁺)/H⁺ antiporter (Lewinson and Bibi 2001; Higgins, 2007). Is known to provide resistance to a wide variety of dissimilar toxic compounds, including neutral, cationic and zwitterionic substances.  Crystals that diffracted to 3.4 Å resolution and belonged to the hexagonal space group P6122 have been obtained (Nagarathinam et al. 2017). For review of MdfA see Lewinson et al., 2006. The conformational switch accompanying transport is induced by the promiscuous binding of substrates and/or inhibitors to the binding pocket (Fluman et al., 2009). MdfA normally extrudes monovalent cationic drugs in exchange for a single proton, but it transports divalent cationic drugs poorly. It can be mutated to antiport a divalent cationic drug for 2 protons (Tirosh et al., 2012). Transporters acting across the inner and outer membranes have synergistic effects with each other, but transporters acting across the same membrane are usually additive but can be synergistic under special circumstances, owing to a bifurcation controlled by the barrier constant (Saha et al. 2020). Promiscuity in the geometry of electrostatic interactions between  MdfA and cationic substrates has been demonstrated (Adler and Bibi 2005). With respect to ethidium bromide, the inner membrane transporter MdfA is synergistic to the TolC-dependent efflux across the outer membrane (Saha et al. 2020). The conformational behavior of MdfA in response to substrate binding has been studied (Bahrenberg et al. 2021). Overexpression of the gene for MdfA allows export of Lacto-N-triose (LNT II) and lacto-N-tetraose (LNT), human milk oligosaccharides (Sugita and Koketsu 2022).