JAC Advance Access originally published online on December 12, 2002
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Journal of Antimicrobial Chemotherapy (2003) 51, 9-11
© 2003 The British Society for Antimicrobial Chemotherapy
Leading Article |
The importance of efflux pumps in bacterial antibiotic resistance
Antimicrobial Agents Research Group, Division of Immunity and Infection, University of Birmingham, Birmingham B15 2TT, UK
Keywords: efflux, multiple antibiotic resistance
Efflux pumps are transport proteins involved in the extrusion of toxic substrates (including virtually all classes of clinically relevant antibiotics) from within cells into the external environment. These proteins are found in both Gram-positive and -negative bacteria as well as in eukaryotic organisms.1 Pumps may be specific for one substrate or may transport a range of structurally dissimilar compounds (including antibiotics of multiple classes); such pumps can be associated with multiple drug resistance (MDR). In the prokaryotic kingdom there are five major families of efflux transporter:2 MF (major facilitator), MATE (multidrug and toxic efflux), RND (resistance-nodulation-division), SMR (small multidrug resistance) and ABC (ATP binding cassette). All these systems utilize the proton motive force as an energy source,3 apart from the ABC family, which utilizes ATP hydrolysis to drive the export of substrates. Recent advances in DNA technology and the advent of the genomic era have led to the identification of numerous new members of the above families, and the ubiquitous nature of efflux pumps is remarkable. Transporters that efflux multiple substrates, including antibiotics, have not evolved in response to the stresses of the antibiotic era. All bacterial genomes studied contain several different efflux pumps; this indicates their ancestral origins. It has been estimated that 
5–10% of all bacterial genes are involved in transport and a large proportion of these encode efflux pumps.2,4
There is some debate as to the ‘normal’ physiological role of efflux transporters, as antibiotic susceptible as well as resistant bacteria carry and express these genes. In many cases, efflux pump genes are part of an operon, with a regulatory gene controlling expression. Increased expression is associated with resistance to the substrates, e.g. resistance to bile salts and some antibiotics in Escherichia coli is mediated by over-expression of acrAB.5 Although genes encoding efflux pumps can be found on plasmids, the carriage of efflux pump genes on the chromosome gives the bacterium an intrinsic mechanism that allows survival in a hostile environment (e.g. the presence of antibiotics), and so mutant bacteria that over-express efflux pump genes can be selected without the acquisition of new genetic material. It is probable that these pumps arose so that noxious substances could be transported out of the bacterium, allowing survival. Indeed it is now widely accepted that the ‘intrinsic resistance’ of Gram-negative bacteria to certain antibiotics relative to Gram-positive bacteria is a result of the activity of efflux systems.6 Efflux systems that contribute to antibiotic resistance have been described from a number of clinically important bacteria, including Campylobacter jejuni (CmeABC7,8), E. coli (AcrAB-TolC, AcrEF-TolC, EmrB, EmrD9), Pseudomonas aeruginosa (MexAB-OprM, MexCD-OprJ, MexEF-OprN and MexXY-OprM9), Streptococcus pneumoniae (PmrA10), Salmonella typhimurium (AcrB11) and Staphylococcus aureus (NorA12). All of these systems efflux fluoroquinolones and the RND pumps (CmeB, AcrB and the Mex pumps) also export multiple antibiotics.
Over-expression of efflux pumps can result from mutations within local repressor genes13–15 or may result from activation of a regulon regulated by a global transcriptional regulator such as MarA or SoxS of E. coli.16,17 The broad substrate range of efflux systems is of concern, as often over-expression of a pump will result in resistance to antibiotics of more than one class as well as some dyes, detergents and disinfectants (including some commonly used biocides). Cross-resistance is also a problem; exposure to any one agent that belongs to the substrate profile of a pump would favour over-expression of that pump and consequent cross-resistance to all other substrates of the pump. These may include clinically relevant antibiotics. An example of this is seen again with the mexAB system of P. aeruginosa; mutants that over-produce MexAB are less susceptible, if not fully resistant to a range of antibiotics (fluoroquinolones, ß-lactams, chloramphenicol and trimethoprim) but also triclosan, a commonly used household biocide.18 The potential misuse of biocides and possible selection of bacteria cross-resistant to antibiotics has recently been debated in this journal and elsewhere.19–22 Over-expression of a multidrug resistance efflux pump alone often does not confer high-level, clinically significant resistance to antibiotics. However, such bacteria are better equipped to survive antibiotic pressure and develop further mutations in genes encoding the target sites of antibiotics.23 It has been shown that fluoroquinolone-resistant strains of E. coli are selected 1000-fold more readily from mar mutants than wild-type bacteria,24 and highly fluoroquinolone-resistant E. coli contain mutations in genes encoding the target topoisomerase enzymes and have reduced accumulation and increased efflux (porin down-regulation and efflux pump over-expression).14,15 Additive increases in MICs of antibiotics have also been seen after concurrent over-expression of more than one pump of different classes, also resulting in highly resistant E. coli.25
It has been demonstrated that expression of the Mex systems of P. aeruginosa and the acrAB efflux system of E. coli is greatest when the bacteria are stressed, e.g. growth in a nutrient-poor medium, growth to stationary phase or osmotic shock; these inhospitable conditions may be relevant to the situation within an infection.26,27 Unregulated over-expression of efflux pumps is potentially disadvantageous to the bacterium as not only will toxic substrates be exported but also nutrients and metabolic intermediates may be lost. Work with P. aeruginosa has suggested that mutants over-expressing Mex pumps are less able to withstand environmental stress and are less virulent than their wild-type counterparts.28 As a result the expression of pumps is tightly controlled. However, mutants and clinical isolates that over-express efflux pumps are stable and commonly isolated; it may be that such mutants accumulate compensatory mutations allowing them to grow as well as wild-type bacteria.
Recently, the use of efflux pump inhibitors has been investigated in order to improve and potentiate the activity of exported antibiotics. Such a strategy has been used to develop inhibitors that reduce the impact of efflux pumps on fluoroquinolone activity. As many efflux pumps possess significant structural homology, it is hoped that one inhibitor compound will be active against a range of pumps from different bacterial species. Most research has focused upon P. aeruginosa Mex efflux pumps and inhibitors of these. One such inhibitor lowered the MIC values of fluoroquinolones for both sensitive and resistant strains.2 In addition the frequency of selection of fluoroquinolone-resistant strains was also lower in the presence of the inhibitor, suggesting that efflux may be important in the selection of fluoroquinolone resistance. Similar observations have been made for S. pneumoniae and S. aureus.29,30 A requirement for an intact efflux system to allow the development of topoisomerase mutations and consequent fluoroquinolone resistance in E. coli has also been described.31 The link between active efflux and mutations in genes encoding the target site proteins suggests that the use of such inhibitors, in association with substrate antibiotics, may be useful by increasing both the activity and the range of species for which a drug may be effective. The design of new drugs and modification of existing molecules should also now be carried out with efflux pumps in mind. Structural alterations that reduce the ability of an antibiotic to be effluxed without compromising its activity may lead to the development of more potent compounds, certainly the ‘effluxability’ of drugs must now be considered, as agents are developed with regard to their overall efficacy and the likelihood of development of resistance.
To conclude, there is increasing evidence that the role of efflux pumps in antibiotic resistance in bacteria is significant. Although high-level resistance may not occur as a result of MDR efflux pumps alone, the association of over-expression of these genes amongst highly resistant clinical isolates cannot be ignored. The intrinsic antibiotic resistance of certain species may also be largely due to efflux pumps. Selection of efflux mutants by biocides encountered in the environment is a potential concern; more work is needed to quantify the risk, if any, from such a process. Synergic increases in resistance seen with over-expression of efflux system(s) as well as target site mutations can lead to highly resistant bacteria that are hard to treat. The effect of efflux pumps needs to be considered in the design of future antibiotics and the role of inhibitors assessed in order to maximize the efficacy of current and future antibiotics.
For those interested, there are a number of excellent review articles focusing on efflux pumps.2,3,9,11,32,33
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Footnotes |
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* Corresponding author. Tel: +44-121-414-6966; Fax: +44-121-414-3599; E-mail: l.j.v.piddock{at}bham.ac.uk
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References |
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