Tetracyclines efflux proteins

Plasmid- or transposon-encoded tetracycline efflux proteins have been described in a number of bacteria. These efflux profeins are fhoughf to span fhe cytoplasmic membrane and are dependenf on the proton-motive force for their action, ft is thought that the efflux proteins bind tetracyclines and initiate proton transfer, although no functional domains have been identified. Eight distinct tetracycline efflux profeins have been idenfified thus far. 

Cheng, J., Hicks, D. B. and Krulwich, T. A. (1996). The purified Bacillus subtilis tetracycline efflux protein TetA(L) reconstitutes both tetracycline-cobalt/H+ and Na+(K+)/H+ exchange, Proc. Natl Acad. Sci. USA, 93, 14446-14451. 

More recently possible roles in supporting pH homeostasis and alkali tolerance have been suggested for TetL, which is a tetracycline efflux protein from Bacillus subtilis, and the multidrug transporter MdfA (71). 

Sheridan RP, Chopra 1, Origin of tetracycline efflux proteins—conclusions from nucleotide-sequence analysis. Mol Microbiol 1991 5 895-900. 

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...

Genes encoding efflux pumps confer resistance to tetracyclines Genes encoding proteins protecting the ribosome from the inhibiting effects of tetracycline... 

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

Resistance is related largely to changes in cell permeability and a resultant decreased accumulation of drug due to increased efflux from the cell by an energy-dependent mechanism. Other mechanisms, such as production of a protein that alters the interaction of tetracycline with the ribosome and enzymatic inactivation of the drug, have been reported. 

Mechanisms of Resistance. Three distinct biochemical mechanisms of resistance to tetracyclines have been identified. The energy-dependent efflux of antibiotic mediated by resistance proteins located in the bacterial... 

Three mechanisms of resistance to tetracycline have been described (1) decreased intracellular accumulation due to either impaired influx or increased efflux by an active transport protein pump (2) ribosome protection due to production of proteins that interfere with tetracycline binding to the ribosome and (3) enzymatic inactivation of tetracyclines. The most important of these is production... 

Tetracycline was effective against gynecologic infection due to bacteroides, but now these organisms are resistant due to the presence of plasmid-mediated protein that promotes efflux of the drug. 

Figure 4.2. Proposed mechanism for tetracycline (TET) uptake and efflux across the bacterial cytoplasmic membrane. Mg, divalent magnesium cation TH2 and TH, protonaled and deproton-ated tetracycline, respectively TH Mg, magnesium-tetracycline chelate complex. Tet proteins confer resistance to tetracycline by mediating expulsion ofTH Mg from the cell in exchange for a...

Plasmid-mediated resistance to QACs and chlorhexidine in S. aureus has been cloned in E. coli [302] but the level of resistance is low and the mechanism not fully elucidated. The efflux-mediated antiseptic resistance gene qacA from S. aureus has a common ancestry with tetracycline- and sugar-transported proteins [227-229]. 

S. B., Inhibition of the tetracycline efflux antiport protein by 13-thio-substituted 5-hy-droxy-6-deoxytetracycline, J. Med. Chem... 36,. 370, 199.3. 

Resistance is widespread and often is indncible. The three main resistance mechanisms are (1) decreased accumulation of tetracycline (decreased antibiotic influx or acquisition of an energy-dependent efflux pathway) (2) production of a ribosomal protein that displaces tetracycline from its target, a protection that also may occur by mutation and (3) enzymatic inactivation of tetracyclines. Cross-resistance amongst tetracyclines depends on which mechanism is operative. Tetracycline resistance due to a ribosomal protection mechanism produces cross-resistance to doxycycUne and minocycline because the target site protected is the same for all tetracyclines. 

Selective toxicity of these protein synthesis inhibitors against microorganisms may be explained by target differences. Chloramphenicol does not bind to the SOS ribosomal RNA of mammalian cells, though it can inhibit the functions of mitochotidrial ribosomes, which contain 70S ribosomal RNA. Tetracyclines have little effect on mammalian protein synthesis because an active efflux mechanism prevents their intracellular accumulation. 

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