Multidrug Transport Mechanisms in Membrane Proteins

Membrane proteins that mediate the extrusion of structurally diverse compounds are central to multidrug resistance across bacteria, fungi and higher organisms. These transporters employ secondary active mechanisms, harnessing ion gradients—most commonly protons or sodium ions—to drive the efflux of antibiotics, antiseptics and xenobiotics. Major protein families include the ATP‐binding cassette (ABC) transporters, the major facilitator superfamily (MFS), the small multidrug resistance (SMR) proteins and the multidrug and toxic compound extrusion (MATE) family. A unifying concept is the alternating‐access mechanism, in which conformational changes expose the substrate‐binding site alternately to the cytoplasm and the extracellular milieu. Structural studies have revealed critical roles for conserved acidic or aromatic residues, interdomain linkages and extracellular loops in substrate recognition and coupling stoichiometry. Insights into these mechanisms inform the design of efflux inhibitors, guide optimisation of drug pharmacokinetics and underpin biotechnological strategies to enhance microbial tolerance to valuable bioproducts.

Research from Nature Portfolio

Recent high‐resolution cryo‐electron microscopy has unveiled the proton‐coupling mechanism of a Staphylococcus aureus efflux pump by capturing multiple protonation states of two essential acidic residues. This work demonstrated that protonation of a glutamate–aspartate pair stabilises an inward‐occluded conformation, while their concerted deprotonation triggers opening of the substrate pocket, enforcing strict coupling stoichiometry and preventing simultaneous proton and drug binding. Equally transformative are solid‐state NMR studies of a dimeric small multidrug transporter reconstituted in lipid bilayers. By mapping over two hundred protein–substrate distances, the drug‐bound structure revealed a spacious aromatic‐rich binding cavity and asymmetric proximity of the substrate to a key glutamate in one subunit, offering a molecular basis for promiscuous recognition and the asymmetric protonation that drives transport.

Multidrug Transport Mechanisms in Membrane Proteins publication trend

The graph below shows the total number of articles in multidrug transport mechanisms in membrane proteins across all publications each year (not limited to Nature Index journals).

Technical terms

Efflux pump: A membrane protein that exports diverse substrates from cells, often using ion gradients.

Antiporter: A transporter that exchanges one substrate for another across the membrane in opposite directions.

Alternating‐access mechanism: A model in which substrate‐binding sites are alternately accessible to either side of the membrane.

Proton motive force: The electrochemical gradient of protons across a membrane, used to drive transport.

Major facilitator superfamily (MFS): A large family of secondary transporters that move small solutes in response to ion gradients.

Small multidrug resistance (SMR) proteins: Compact four‐helix antiporters that efflux toxic cations in exchange for protons.

Cryo‐electron microscopy: A structural method that images proteins at near‐atomic resolution in a frozen, native‐like state.

References

1. Proton-coupled transport mechanism of the efflux pump NorA. Nature Communications (2024).
2. Cryo‐EM structure of antibacterial efflux transporter QacA from Staphylococcus aureus reveals a novel extracellular loop with allosteric role. The EMBO Journal (2023).
3. Identification and expression of small multidrug resistance transporters in early‐branching anaerobic fungi. Protein Science (2023).
4. Structure and dynamics of the drug-bound bacterial transporter EmrE in lipid bilayers. Nature Communications (2021).
5. Multidrug Transport Protein NorM from Vibrio cholerae Simultaneously Couples to Sodium- and Proton-Motive Force*. Journal of Biological Chemistry (2014).