Efflux resistance

Jacob, M.R., Hossain, C.F., Mohammed, K.A., SmiDie, T.J., Clark, A. M., Walker, L.A., and Nagle, D.G. (2003) Reversal of fluconazole resistance in multidrug efflux-resistant fimgi by the Dysidea arenaria sponge sterol 9a,lla,-epoxycholest-7-ene-3p,5a,6a,19-tetrol-6-acetate. J. Nat. Prod., 66,1618-1622. 

Fig. 4. Comparison of the three types of tetracycline resistance where T represents the tetracycline molecule O, a tetracycline transporter and aaa/, the ribosome A shows the effect of tetracycline exposure on a sensitive cell B, the efflux of resistance where a cytoplasmic membrane protein ( D) pumps tetracycline out of the cell as fast as the tetracycline transporter takes it up C, the ribosomal protection type of resistance where the ribosome is modified by ( ) to block productive binding and D, the tetracycline modification type of resistance where t is an inactive form of tetracycline. Reproduced with...

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. 

Li X-Z, Nikaido H (2004) Efflux-mediated drug resistance in bacteria. Drugs 64 159-204... 

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

The second general mechanism to cause resistance to antibacterial agents is to prevent the drug from reaching its target site. This is either achieved by altered rates of entry (reduced uptake) or by the active removal of the dtug (active efflux) [4]. 

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]... 

Multidrug Resistance Transporters (Efflux) (e.g. P-gp. BCRF, MRP) MoDocarboxylic Acid Transporters (Efflux) (e.g. MCTl, MCT2)... 

Both influx and efflux transporters are located in intestinal epithelial cells and can either increase or decrease oral absorption. Influx transporters such as human peptide transporter 1 (hPEPTl), apical sodium bile acid transporter (ASBT), and nucleoside transporters actively transport drugs that mimic their native substrates across the epithelial cell, whereas efflux transporters such as P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP), and breast cancer resistance protein (BCRP) actively pump absorbed drugs back into the intestinal lumen. 

Breast cancer resistance protein (BCRP) is another ATP-dependent efflux transporter that confers resistance to a variety of anticancer agents, including... 

A more recently recognized mechanism of dmg resistance is that of efflux in which the antibiotic is rapidly extmded horn the cell by an energy-dependent mechanism. This affects antibiotics such as the tetracyclines and macrolides. 

Fig. 9.1 Schematic representation of possible mechanisms of resistance in Gram-negative and Gram-positive bacteria. 1, antibiotic-inactivating enzymes 2, antibiotic efflux proteins 3, alteration or duplication of intracellular targets 4, alteration of the cell membrane reducing antibiotic uptake 5, alterations in porins or lipopolysaccharide reducing antibiotic uptake or binding.

Resistance to quinolones by efflux has been described in Staph, aureus and Proteus mirabilis. This gene has been designated nor A in Staph, aureus and is homologous to membrane transport proteins coupled to the electromotive force. These proteins have the ability to remove small amounts of quinolone from cells normally and nor A may have arisen as a result of mutations under selective pressure from quinolone use, resulting in a transport protein with increased affinity for these agents. 

A gene designated msrA has been identified in Staph, aureus which confers resistance to macrolides and streptogramins but not to lincosamides. Its function is unknown but the DNA sequence is homologous to genes coding for known efflux proteins. 

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