**5. Conclusion**

all the β-lactam drugs and are not inactivated by the standard β-lactam/β-lactamase inhibitor combination drugs. There is a newer β-lactamase inhibitor, avibactam, which has been approved for use with ceftazidime against gram-negative bacteria. In addition, avibactam is

Bacteria possess methods for disposal of toxic substances to the outside of the cell. The most commonly used mechanism is the efflux pump. Most bacteria have chromosomally encoded efflux pump genes. Some of these pumps are expressed constitutively, and expression of others is induced by various environmental stimuli. Many of these pumps are capable of transporting a variety of substances and are also described as multidrug (MDR) efflux pumps. There are five efflux pump family groups: the ATP-binding cassette (ABC) family, the multidrug and toxic compound extrusion (MATE) family, the major facilitator superfamily (MFS), the small multidrug resistance (SMR) family, and the resistance-nodulationcell division (RND) family. The RND pumps are generally found only in gram-negative bacteria as these pumps are multicomponent pumps that function in association with an

There is only one ABC efflux pump in *E. coli* that is known to contribute to antimicrobial resistance. That is the MacAB transporter that confers resistance to some macrolides [73]. There is also only one MATE efflux pump found in *E. coli*, the NorE pump which is able to transport fluoroquinolones. It is still in question if the NorE pump has a clinically significant impact on antimicrobial resistance [74, 75]. There are five known MFS efflux pumps found in *E. coli*. These are capable of transporting macrolides (MefB and MdfA pumps), fluoroquinolones (QepA2, EmrAB-TolC, and MdfA pumps), tetracycline (EmrAB-TolC and MdfA pumps), trimethoprim (Fsr pump), and chloramphenicol (MdfA pump). In addition, there are several MFS pumps that may be acquired by *E. coli* (e.g., via plasmids) that are specific for tetracyclines, with *tetA* and *tetB* being the most common [76, 77]. There are no clinically

The RND efflux pumps are the most clinically significant pumps found in gram-negative bacteria. These pumps consist of three components (tripartite): an inner membrane transporter, an outer membrane porin, and a periplasmic accessory protein that functions to connect the other two components. In *E. coli*, the OMP that is associated with all of the antimicrobial efflux pumps is TolC. There are five known RND pumps in *E. coli*: AcrAB-TolC, AcrAD-TolC, AcrEF-TolC, MdtABC-TolC, and MdtEF-TolC. AcrAD-TolC has been shown to efflux aminoglycosides and β-lactams. AcrEF-TolC has been shown to efflux quinolones and tigecycline. MdtABE-TolC has been shown to efflux quinolones. MdtEF-TolC has been shown to efflux erythromycin. The level of expression of these four pumps is relatively low, and if operating alone, the amount of antimicrobials effluxed would probably not be significant. Because *E. coli* has five efflux systems plus multiple other types of antimicrobial resistance mechanisms in play, these pumps undoubtedly help out. The other RND efflux pump in *E. coli*, AcrAB-TolC, is the most clinically significant and accounts for major antimicrobial efflux. This pump has been shown to efflux β-lactams, fluoroquinolones, tetracyclines, chloramphenicol, and lincos-

being tested for use with aztreonam against CREs [62, 66–68].

90 *Escherichia coli* Escherichia coli - Recent Advances on Physiology, Pathogenesis and Biotechnological Applications - Recent Advances on Physiology, Pathogenesis and Biotechnological Applications

significant SMR efflux pumps found in *E. coli* [78].

**4.4. Drug efflux**

OMP [69–72].

amides [72, 79, 80].

For many strains of pathogenic *E. coli*, the most common course of therapy is supportive and does not require the use of antimicrobial drugs, or in the case of EHEC, antimicrobial therapy is not recommended. For severe intestinal infections and UTIs, antimicrobial therapy may be necessary. Unfortunately with the issue of ever increasing antimicrobial resistance, the antimicrobial options are becoming fewer. With the emergence of ESBL and CRE *E. coli* strains, the options have gotten extremely limited, and antimicrobial development has not been able to keep up with the demand. Hopefully the newer carbapenem/β-lactamase inhibitor combination drugs and other drugs being developed under the tetracycline and aminoglycoside drug classes will prove to be equal to the task or at least keep the bacteria under control until better options become available.
