The Multidrug Resistance Transporters

Obviously, not all predicted transporters are being confirmed to be polyspecific, but quite a few of them are [15], underscoring the impressive scale of the bacterial resistome. We should consider ourselves lucky that not all of these polyspecific transporters, frequently dubbed MDRs, are in fact clinically relevant. While they effectively expel dyes, quaternary ammonium compounds, and other organic 

In this by no means comprehensive overview, we examine the families of bacterial polyspecific transporters and features of their structure and transport mechanisms that make them particularly efficient in preventing antibiotics access to their targets. 

We discuss their impact on antibiotic effectiveness in clinical settings and on anti-infective drug discovery. Finally, we describe some humble efforts to outsmart mother nature. 

An enormous amount of information on bacterial efflux transporters has been summarized in several recent excellent review articles, addressing various aspects of the efflux problem, such as the origin and evolution of efflux pump [16], mechanisms of multidrug recognition [10,17], regulation of expression of MDR pumps [18-20], natural functions of MDR pumps [21], and clinical aspects of MDR [22-24]. 

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Hollo, Z., Homolya, L., Davis, C.W. and Sarkadi, B. (1994) Calcein accumulation as a fluorometric functional assay of the multidrug resistance transporter. Biochimica et Biophysica Acta, 1191, 384-388. 

Fellay J, Marzolini C, Meaden E, Back D, Buclin T, Chave J, Decosterd LA, Furrer H, Opravil M, Pantaleo G, Retelska D, Ruiz L, Schinkel AH, Vernazza P, Eap CB, Telenti A. Response to antiretroviral treatment in HIV-1-infected individuals with allelic variants of the multidrug resistance transporter 1 a pharmacogenetics study. Lancet 2002 359 30-36. 

Cui, Z., Shiraki, T., Hirata, D., and Miyakawa, T. (1998) Yeast gene YRRl, which is required for resistance to 4-nitroquinoline N-oxide, mediates transcriptional activation of the multidrug resistance transporter gene SNQ2. Molecular Microbiology, 29. 1307-1315. 

Swiss HIV Cohort Study, Response to antiretroviral treatment in HIV-l-infected individuals with allelic variants of the multidrug resistance transporter 1 a pharmacogenetics study. Lancet 2002 359(9300) 30-36. 

The breast cancer resistance protein (BCRP) belongs to the G-branch of the ABC-transporter family (ABCG2). In contrast to most other ABC-proteins, BCRP consists of only one transmembrane domain (TDM) with one nucleotide binding fold (NBF) at its C-terminus. Because of this structural characteristic BCRP as well as other ABC-transporters with only one TMD are termed half transporters. To achieve functional activity these transporters have to form hetero- or homodimers. BCRP is involved in the multidrug resistance of certain tumors and transports endogenous compounds like cholesterol and steroid hormones. 

The multidrug resistance (MDR) phenomenon has first been described in cancer cells which were resistant against several structurally unrelated anticancer dtugs. Mechanistically a high expression of different ABC-transporters (P-gp, MRP) has been identified as the underlying factor. 

Chearwae, W. et al.. Modulation of the function of the multidrug resistance-linked ATP-binding transporter ABCG2 by the cancer chemopreventive agent curcumin. Mol. Cancer Then, 5, 1995, 2006. 

Borst, P., et al. A family of drug transporters the multidrug resistance-associated proteins. J. Natl. Cancer Inst. 2000, 92, 1295-1302. 

H. J., Pinedo, H. M., Feller, N., Dekker, H., Lankelma, J., Giaccone, G., Cortisol is transported by the multidrug resistance gene product... 

Chang, G., Roth, C. B., Structure of MsbA from E. coli a homolog of the multidrug resistance ATP binding cassette (ABC) transporters, Science 2001, 293, 1793-1800. 

Fetsch P, Abati A, Ross DD et al. The multidrug-resistant phenotype associated with overexpression of the new ABC half-transporter, MXR (ABCG2). J Cell Sci 2000 113(Pt 11) 2011-2021. 

The presence at the BBB of members of the multidrug resistance-associated protein (MRPs) family, whose members preferentially transport anionic compounds, is still controversial. The seven members of the MRP family belong, like P-gp, to the ATP-binding cassette (ABC) protein superfamily. Mrpl has been found at the BBB in isolated rat brain capillaries, primary cultures of brain capillary endothelial cells and in immortalized capillary endothelial cells, but not in human brain capillaries [59]. Another member, MRP2 has been found at the luminal membrane of the brain endothelial cells [60]. However, further studies are required to show that there are MRP transporters at the BBB (Figure 15.5). As for P-gp, a functional Mrpl was found in primary cultured rat astrocytes [56] and it has been shown to take part in the release of glutathione disulfide from brain astrocytes under oxidative stress [61]. 

J. A family of dmg transporters The multidrug resistance-associated proteins. 

Van Luyn MJA, Muller M, Renes J, Meijer C, Scheper RJ, Nienhuis EF, Mulder NH, Jansen PLM, De Vries EGE (1998) Transport of glutathione conjugates into secretory vesicles is mediated by the multidrug-resistance protein 1. Int J Cancer 76 55-62 Vermeij G (1994) The evolutionary interaction among species selection, escalation, and coevolution. Annu Rev Ecol Syst 25 219-236... 

Grzywacz, M.J., Yang, J.M. and Hait, W. N. (2003) Effect of the multidrug resistance protein on the transport of the antiandrogen flutamide. Cancer Research, 63, 2492-2498. 

Jedlitschky, G., Leier, I., Buchholz, U., Center, M. and Keppler, D. (1994) ATP-dependent transport of glutathione S-conjugates by the multidrug resistance-associated protein. Cancer Research, 54, 4833—4836. 

Renes, J., deVries, E.G., Nienhuis, E.F., Jansen, P.L. and Muller, M. (1999) ATP-and glutathione-dependent transport of chemotherapeutic drugs by the multidrug resistance protein MRP1. British Journal of Pharmacology, 126, 681-688. 

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