Efflux pump

Two mechanisms are operating alone or in concert to minimize the antibiotic concentration at the intracellular target site Downregulation of the expression of the pore proteins, also called porins, and upregulation of one or a set of several unspecific efflux pumps. However, the impact of these mechanisms on the resistance is low, since due to the essential function of porins for uptake of nutrients their reduction is limited and to avoid disturbances of membrane integrity due to extensive oveiproduction of mdr efflux pumps these are subjected a strict regulation. 

Currently, five different molecular classes of mdr efflux pumps are known [5], While pumps of the the ATP-binding cassette (ABC) transporter superfamily are driven by ATP hydrolysis, the other four superfamilies called resistance-nodulation-division (RND), major facilitator superfamily (MFS), multidrug and toxic compound extrusion (MATE), and small multidrag resistance transporter (SMR) are driven by the proton-motive force across the cytoplasmic membrane. Usually a single pump protein is located within the cytoplasmic membrane. However, the RND-type pumps which are restricted to Gram-negative bacteria consist of two additional components, a periplasmic membrane fusion protein (MFP) which connects the efflux pump to an outer... 

The combined intrinsic activities of different efflux pumps play a major role for the intrinsic resistance of Gram-negative bacteria to macrolides and oxazolidi-nones as well as to the intrinsic resistance of Pseudomonas aeruginosa against a broad range of disinfectants and antibiotics. 

Acquired resistance has been observed by constitutive upregulation of mdr efflux pump expression due to a mutation inactivating a respective repressor or inducibly, caused by molecules transiently inactivating repressor molecules upon binding. Depending upon the substrate spectra of the respective subset of efflux pumps upregulated, a multiple drug resistance (mdr) phenotype is expressed, which in combination with a specific resistance mechanism can contribute to a clinically relevant level of resistance. 

Mdr-1 Drug-efflux pump Reduction in resistance to chemotherapeutic drugs... 

ATP-binding cassette (ABC) transporters are efflux pumps that derive the energy needed for drug extrusion from the hydrolysis of ATP. Bacterial ABC antibiotic efflux transporter encoded on plasmids is a significant... 

Although nucleoside analogs are not substrates for P-gp or CYP3A4, most protease inhibitors and NNl are substrates for both the P-gp efflux pump (Aungst 1999 ... 

Except for its narrow specificity, the ATRI gene product shares a number of properties with the higher eukaryotic MDR proteins responsible for multidrug resistance in tumour cells. The MDR gene products are also transmembrane proteins which seem to function as ATP-dependent drug-efflux pumps pumping out a variety of structurally unrelated compounds (see [25,26]). 

Kieboom, J, JJ Dennis, JAM de Bont, GJ Zylstra (1998) Identification and molecular characterization of an efflux pump involved in Pseudomonas putida S12 solvent tolerance. J Biol Chem 273 85-91. 

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

Rojas A, E Duque, G Mosqueda, G Golden, A Hurtado, JL Ramos, A Segura (2001) Three efflux pumps are required to provide efficient tolerance toluene in Pseudomonas putida DOT-TIE. J Bacteriol 183 ... 

Turner RJ, Y Hou, JH Weiner, DE Taylor (1992) The arsenical APTase efflux pump mediates tellurite resistance. J Bacteriol 174 3092-3094. 

In some cases, catechins can also act in synergistic mode when used in association with currently used antibiotic molecules (Table 2). EGCG exhibited synergy with /3-lactams. Sudano Roccaro et al. [73] found that this compound is able to reverse tetracycline resistance in Staphylococcus epidermidis and S. aureus isolates. This synergistic interaction has been explained by inhibition of tetracycline efflux pump activity in microbial cells resulting in an... 

Tumor cells may become resistant when genetic changes occur during cell proliferation. Resistant cancer cells with the mdr-1 gene may possess a membrane-associated protein, p-glycoprotein, that facilitates efflux of chemotherapy agents out of the cells. Numerous attempts at blocking this efflux pump have been unsuccessful. 

In microbes without a permeability barrier, or when the barrier fails, a mechanism must be in place to export metals from the cytoplasm. These active transport systems involve energy-dependent, membrane-bound efflux pumps that can be encoded by either chromosomal- or plasmid-borne genes. Active transport is the most well-studied metal resistance mechanism. Some of these include the ars operon for exporting arsenic from E. coli, the cad system for exporting cadmium from Staphylococcus aureus, and the cop operon for removing excess copper from Enterococcus hiraeP i9A0... 

P Saha, J Yang, VHL Lee. (1998). Existence of a p-glycoprotein drug efflux pump in cultured rabbit conjunctival epithelial cells. Invest Opthalmol Vis Sci 39 1221-1226. 

The use of Caco-2 cell monolayers has gained in popularity as an in vivo human absorption surrogate moreover, the monolayers are generally accepted as a primary absorption screening tool by several pharmaceutical companies [10]. However, Caco-2 cell permeability measurements exhibit certain limitations due to the mechanisms involved. Both passive and active pathways exist active transport tends to increase the absorption across the cells and, since Caco-2 cells overexpress the P-glycoprotein (P-gp) efflux pump, the absorption of some compounds across these cells may be underestimated. 

Chen, Y., Simon, S. M., In situ biochemical demonstration that P-glyco-protein is a drug efflux pump with broad specificity, J. Cell Biol. 2000,... 

Breast Cancer Resistance Protein (BCRP, also known as MXR or ABCP), first cloned from mitoxantrone and anthracycline-resistant breast and colon cancer cells [188, 189] is a half-transporter efflux pump believed to function as a homo-or hetero-dimer. Following its identification, BCRP-mediated drug resistance was observed for topoisomerase inhibitors including camptothecins [190, 191] and in-dolocarbazoles [192]. In normal tissues, BCRP was detected in placental syncytio-trophoblasts, hepatocyte canalicular membrane, apical intestinal epithelia and vascular endothelial cells [193]. These findings support the important role BCRP plays in modulating topotecan bioavailability, fetal exposure and hepatic elimination [194]. Considering that the substrates and tissue distributions for BCRP overlap somewhat with MDR1 and MRPs [195], additional studies will be required to define the relative contribution of each of these transporters in the overall and tis-... 

Bacteria possess biological efflux pumps that involve an energy-dependent export of antibiotics, among other substances, from within either the periplasm or cytoplasm to the outside environment. This is essentially a detoxification process for the bacteria. The phenomenon decreases the concentration of antibiotic inside the cell [7]. 

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