Diversity of Bacterial MDR Efflux Systems

ABC MDRs (as all other members of this superfamily) are primary active transporters that couple substrate translocation to binding and hydrolysis of ATP. M D Rs in all the other superfamilies are secondary transporters that use electrochemical gradients of ions (most frequently protons but sometime sodium) to transport their diverse substrates. Both primary and secondary transporters are ubiquitous in bacteria li owcvcr, their relative presence seems to correlate with energy generation fermentative bacteria tend to rely more on the primary transporters while aerobic bacteria contain somewhat more secondary transporters in their genomes [32, 33]. 

While being polyspecific, bacterial MDRs from different families are still vastly different in the level of promiscuity toward various substrates. Nonetheless, some substrates such as hydrophobic cations, for example, ethidium bromide, can be handled by a majority of them. Bacteria have apparently evolved with special care to ensure protection against such compounds. Such compounds have the potential to be particularly harmful. If not intercepted, they can accumulate intracellularly, driven by the inside negative membrane potential. Perhaps not by coincidence but exactly because of this extra precaution taken by bacteria long ago, hydrophobic cations are conspicuously absent from the list of clinically useful antibiotics [34]. 

All ABC transporters contain four essential modules, two nucleotide binding domains (N BDs) and two transmembrane domains (TMDs). These four modules can be encoded by four separate genes or fused pairwise in all possible combinations [35, 37]. Bacterial MDRs are usually homo- or heterodimers in which one NBD is fused to one TMD. This is the case for the most well-studied bacterial ABC MDRs, LmrA [38] and LmrCD [39], both from Lactococcus lactis. 

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