Efflux system

Bacterial resistance can be caused by actively pumping antibiotics out of the cell and therefore decreasing the concentration at the target site. Drug efflux systems in bacteria are classified into four major groups based on their sequence homologies and functional similarities (Table 3). 

Microbial Resistance to Drugs. Table 3 Examples of frequent bacterial efflux systems [4]... 

An alternative to most of these mechanisms is the existence of efficient efflux systems, so that toxic concentrations of the drug are not achieved. There are three major families of proton-dependent multidrug efflux systems (1) the major facilitator superfamily, (2) the small multidrug resistance family, and (3) the resistance/nodulation/cell division family (Paulsen et al. 1996). It should be emphasized that several of these systems are involved not with antibiotic efflux but with, for example, acriflavine, chlorhexidine, and crystal violet. An attempt is made only to outline a few salient features of the resistance/nodulation/cell division family that mediates antibiotic efflux, and these are given in Table 3.3 (Nikaido 1996). They consist of a transporter, a linker, and an outer membrane channel. 

Hearn EM, JJ Dennis, MR Gray, JJ Foght (2003) Identification and characterization of the emhABC efflux system for polycyclic aromatic hydrocarbons in Pseudomonas fluorescens cLP6a. J Bacterial 185 6233-6240. 

Li X-Z, L Zhang, K Poole (1998) Role of multidrug efflux systems of Pseudomonas aeruginosa in organic solvent tolerance. J Bacterial 180 2987-2991. 

Paulsen IT, MH Brown, RA Skurray (1996) Proton-dependent multidrug efflux systems. Microbiol Rev 60 575-608. 

Nies, D.H. and Silver, S., Ion efflux systems involved in bacterial metal resistances, J Ind Microbiol... 

Franke, S., Grass, G., Rensing, C., and Nies, D.H., Molecular analysis of the copper-transporting efflux system CusCFBA of Escherichia coli, J Bacteriol, 185 (13), 3804-3812, 2003. 

Hunter, J., Hirst, B. H., Intestinal secretion of drugs the role of P-glycoprotein and related drug efflux systems in limiting oral drug absorption, A dr. Drug Del. Rev. 1997, 25, 129-157. 

Nerurkar, M. M., Burton, P. S., Borchardt, R. T., The use of surfactants to enhance the permeability of peptides through Caco-2 cells by inhibition of an apically polarized efflux system,... 

Saitoh, H., Aungst, B. J., Possible involvement of multiple P-glyco-protein-mediated efflux systems in the transport of verapamil and other organic cations across rat intestine, Pharm. Res. 1995, 12, 1304-1310. 

MIC > 64 ig/ml) against other bacterial species tested. MIC values were elevated in a Murl overexpressing strain but unaffected by overexpressing H. pylori efflux systems [88]. 

For the internalisation of metals, many examples exist for which transport may be coupled to an energy-dependent process, of which only a few are described here. For example, the well-studied (e.g. [276]) Na+/K+ channel transports 3Na+ out and 2K+ in for each ATP molecule that is hydrolysed [242]. Mg2+ influx (but likely not efflux) is highly regulated in eukaryotes [277]. ATPases have been implicated in certain cases of Fe [278] or Zn [90] uptake by phytoplankton. Finally, although Cd internalisation by a polychaete appeared to be energy independent, accumulation was increased rather than decreased in the presence of ATPase inhibitors, suggesting that the efflux system might depend upon ATP synthesis [279]. 

Many drugs have been recognized to cross the intestinal epithelial cells via passive diffusion, thus their lipophilicity has been considered important. However, as described above, recent studies have demonstrated that a number of drug transporters including uptake and efflux systems determine the membrane transport process. In this chapter, we provide an overview of the basic characteristics of major drug transporters responsible not only for absorption but also for disposition and excretion in order to delineate the impact of drug transport proteins on pharmacokinetics. 

Other cell lines used in permeability studies include the T84 human colonic adenocarcinoma colonic crypt cell model. This line has a reduced carrier expression, secrets mucus, and has very high resistance [31, 32], The IEC cell line is a rat fetal intestinal epithelium cell with higher permeabilities than Caco-2 cells [33], LLC PKi is a pig kidney epithelial cell line with low expression of efflux systems, but expression systems for transport proteins [32], 2/4/A1 cells are a conditionally immortalized rat fetal intestinal epithelium line with crypt cell-like morphology and temperature-sensitive differentiation [34], They form differentiated monolayers with tight junctions, increased brush border enzymes when grown on extracellular matrices with laminin. Transport of drugs with LP in 2/4/A1 monolayers was comparable to that in the human jejunum and up to 300 times faster than that in Caco-2 monolayers. In contrast, the permeability of HP drugs was comparable in both cell lines [34],... 

Gene encoding a repressor protein, which regulates the tetracycline efflux system genes Trimethoprim... 

---