Summary

This is a summary of the key points we have presented on our blog, including the 'take home' message in understanding the mechanisms of a multimeric drug transporter such as AcrB.

• AcrB is a homotrimer that functions within a tripartite system with TolC and AcrA.
• AcrB confers upon Gram-negative bacteria the intrinsic ability to efflux and consequential resistance to a broad range of drugs. 
• Drug binding to AcrB monomers is dependent on the molecular weight of the drugs, broadly divided into low and high MW
• Low MW drugs bind directly to the distal binding pocket in the binding monomer before efflux.
• High MW drugs first bind to the access monomer in the proximal binding pocket before being channelled to the distal binding pocket.
• The larger size of high MW drugs and also the positioning of a Phe-617 loop between the proximal and distal binding sites of AcrB prevents the spontaneous transport of high MW drugs into the proximal binding pocket in the binding state.
• Phe-617 blocks the channel connecting the 2 binding sites, making it too narrow for a high MW drug to navigate through.
• The positioning of the Phe-617 loop is dependent on the structure of the high MW drug and may overlap into the distal binding site
• Observed in the binding of rifampicin and erythromycin to AcrB.
• AcrB overcomes this difficulty by inducing a conformational change within its structure to shift from an access state to a binding state - dynamic drug efflux.
• Dynamic drug efflux forces drug molecules through the channel into the distal binding site
• Molecules are subsequently directed into the TolC channel for release into the extracellular environment.

We hope that this research will drive further interest in understanding the mechanisms that guide the function of multimeric drug transporters. AcrB is only one of the many homologues responsible for providing drug resistance to Gram-negative bacteria. Understanding how they work will be pertinent to development of future drugs intended to bypass this problem and effectively kill these bacteria in treatments. Further experiments will be necessary to accomplish this. One mechanism we can propose to deactivate AcrB is to use a homologue of the drug that will bind to the distal or proximal binding site to induce a non-competitive inhibition that will inactivate the AcrB.