Structure, function and inhibition of RND efflux pumps in Gram-negative bacteria: an update

Resistance nodulation division efflux systems have a major role in both intrinsic and acquired multi-drug resistance in Gram-negative bacteria. The recent structure of an assembled tripartite system, AcrAB-ToIC, revealed that AcrB is docked onto ToIC, which remains in an open state once part of the assembled complex and three AcrA molecules complete the structure. This is in contrast to data for the MexAB-OprM system of P. aeruginosa that, depending on pH, has between two and six MexA molecules per OprM trimer. RND systems are also important for pathogenicity of several bacteria and for Salmonellae lacking components of AcrAB-ToIC, expression of known virulence determinants were significantly altered. The importance of these systems in both MDR and pathogenicity has made RND systems the target of new drugs aimed at inhibiting their function. The wealth of new structural and functional data will inform rational drug design.