Antibiotic efflux pumps in prokaryotic cells: occurrence, impact on resistance and strategies for the future of antimicrobial therapy

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Abstract
Originally described in bacteria, drug transporters (or efflux pumps) are now recognized as major determinants in the modulation of the accumulation and efflux of antibacterials in virtually all cell types, from prokaroytes to superior eukaryotes. Transport proteins are in fact major cellular products. Based on sequence similarities with known transporters and with proteins possessing at least two transmembrane segments, it has been calculated that 15–20% of the genome of Escherichia coli or of Saccharomyces cerevisiae may code for this type of protein.1 At least 300 gene products are proposed to transport known substrates effectively, out of which ∼20–30 transport antibiotics and other drugs.2 Figure 1, on this basis, identifies the main groups of transporters (also referred to as superfamilies) that have been shown so far to act effectively upon antibiotics. Two of these superfamilies [major facilitator superfamily (MFS) and ATP binding cassette superfamily (ABC)] span the prokaryote–eukaryote boundary, but with specific members in each kingdom. It must be remembered, however, that most transporters have been identified only very recently, so that the discovery of many more families, with both prokaryotic and eukaryotic members, would not be surprising in the near future. Efflux pumps usually consist of a monocomponent protein with several transmembrane spanning domains (most often 12 of them). However, in Gram-negative bacteria, which are protected by an outer membrane, efflux transporters can be organized as multicomponent systems, in which the efflux pump located in the inner membrane works in conjunction with a periplasmic fusion protein and an outer membrane protein (Figure 2).3 This first review focuses on the impact for antibiotic treatments of efflux pumps found in prokaryotes, while the companion paper4 examines those characterized in eukaryotes.

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