Multidrug efflux

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. 

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. 

Nikaido H (1996) Multidrug efflux pumps in Gram-negative bacteria. J Bacteriol 178 5853-5859. 

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

Koronakis, V., Sharff, A., Koronakis, E., Luisi, B. and Hughes, C. (2000). Crystal structure of the bacterial membrane protein TolC central to multidrug efflux and protein export, Nature, 405, 914—919. 

Murakami, S., Nakashima, R., Yamashita, E. and Yamaguchi, A. (2002). Crystal structure of bacterial multidrug efflux transporter AcrB, Nature, 419, 587-593. 

Chaudhary, P. M., and Roninson, 1. B. (1991) Expression and activity of P-glycoprotein, a multidrug efflux pump, in human hematopoietic stem cells. Cell. 66, 85-94. 

Cherigo L, Pereda-Miranda R, Fragoso-Serrano M, Jacobo-Herrera N, Kaatz GW, Gibbons S (2008) Inhibitors of Bacterial Multidrug Efflux Pumps from the Resin Glycosides of Ipomoea murucoides. J Nat Prod 71 1037... 

H Nikaido. Antibiotic resistance caused by gram-negative multidrug efflux pumps. Clin Infect Dis 27 Suppl 1 32 11, 1998. 

H. E. Jones, I. B. Holland, A. Jacq, T. Wall and A. K. Campbell (2003). Escherichia coli lacking the AcrAB multidrug efflux pump also lacks nonproteinaceous, PHB-polyphosphate Ca2+ channels in the membrane. Biochim. Biophys. Acta, 1612, 90-97. 

Multidrug efflux pumps are tripartite export machines. A complex formed by an inner-membrane transporter and a periplasmic adaptor protein contacts an outer-membrane channel tunnel. Interaction with the adaptor protein leads to an opening of the periplasmic entrance of channel tunnel prerequisite for a successful export. 

Figure 20.7 Multidrug efflux pump. Model of a channel tunnel-dependent export apparatus. Interaction with the adaptor protein opens the entrance of the channel tunnel, allowing export of proteins or drugs. In contrast to the channel tunnel, the structure of the adaptor protein is unknown.

Jr. Structural basis of multiple drug-binding capacity of the AcrB multidrug efflux pump. Science 2003 300(5621) 976-980. 85. 

Mikolosko J, Bobyk K, Zgurskaya HI, Ghosh P. Conformational flexibility in the multidrug efflux system protein AcrA. Structure 2006 14(3) 577-587. 

On the other hand, two newly solved structures of AcrB, which is a well-characterized RND multidrug transporter from Escherichia coli, with and without bound substrates, provide valuable information regarding transport mechanisms of tripartite multidrug efflux systems, alongside newly arising questions (35, 36). Functional implications rising from these publications will be discussed in more detail. 

Kmlwich TA, Lewinson O, Padan E, Bibi E. Do physiological roles foster persistence of drug/multidrug-efflux transporters A case study. Nat. Rev. Microbiol. 2005 3 566-572. 

A multidrug efflux system that appears to be a major contributor to intrinsic high-level resistance to aminoglycosides and macrolides has been identified in Burkholderia pseudomallei (133). 

Enniatins inhibit Pdr5p, one of the major multidrug efflux pumps whose... 

Kaatz GW, Moudgal W, Seo SM, and Kristiansen JE (2003) Phenothiazines and thioxanthenes inhibit multidrug efflux pump activity in Staphylococcus aureus. Antimicrobial Agents and Chemotherapy 47 719-726. 

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