Tetracycline transporter

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...

Aligned sequences of 16 members of the sugar transporter family. Residues which are identical in 5=50% of the 16 sugar-transporter sequences (excluding the quinate transporter (qa-y), the citrate transporter (CIT), the tetracycline transporter (pBR322) and lac permease (LacY)) are highlighted, and recorded below the sequences as CONSERVED . The locations of predicted membrane-spanning helices are indicated by horizontal bars. The sequences were taken from the references cited in the text. 

Studies of other members of the family have also added support to the topological model shown in the Fig. 3. In particular, chemical labelling of the native and mutated tetracycline transporter has confirmed the cytoplasmic location of the N-terminus and the loop connecting transmembrane helices 2 and 3 [231,232]. Protease digestion experiments on this protein have also provided preliminary evidence for the cyto-... 

Although all tetracyclines have a similar mechanism of action, they have different chemical structures and are produced by different species of Streptomyces. In addition, structural analogues of these compounds have been synthesized to improve pharmacokinetic properties and antimicrobial activity. While several biological processes in the bacterial cells are modified by the tetracyclines, their primary mode of action is inhibition of protein synthesis. Tetracyclines bind to the SOS ribosome and thereby prevent the binding of aminoacyl transfer RNA (tRNA) to the A site (acceptor site) on the 50S ri-bosomal unit. The tetracyclines affect both eukaryotic and prokaryotic cells but are selectively toxic for bacteria, because they readily penetrate microbial membranes and accumulate in the cytoplasm through an energy-dependent tetracycline transport system that is absent from mammalian cells. 

Tetracyclines bind to the 305 ribosomal subunit and interfere with bacterial protein synthesis. They are bacteriostatic at normal therapeutic concentrations, but bactericidal at high concentrations. They enter bacteria by passive diffusion and an active carrier-mediated process. Mammalian cells do not possess the tetracycline transport mechanism. The tetracyclines are most active at acidic pH, which is of benefit in the treatment of abscesses. 

Tetracyclines enter microorganisms in part by passive diffusion and in part by an energy-dependent process of active transport. Susceptible cells concentrate the drug intracellularly. Once inside the cell, tetracyclines bind reversibly to the 30S subunit of the bacterial ribosome, blocking the binding of aminoacyl-tRNA to the acceptor site on the mRNA-ribosome complex (Figure 44-1). This prevents addition of amino acids to the growing peptide. 

Antiporter or ion exchange transporters are also common. For example, E. coli uses a metal ion-tetracycline / H+ transporter to carry the antibiotic tetracycline out of cells. This protein, when present, provides a high level of antibiotic resistance to the bacteria.444... 

How do antibiotics act Some, like penicillin, block specific enzymes. Peptide antibiotics often form complexes with metal ions (Fig. 8-22) and disrupt the control of ion permeability in bacterial membranes. Polyene antibiotics interfere with proton and ion transport in fungal membranes. Tetracyclines and many other antibiotics interfere directly with protein synthesis (Box 29-B). Others intercalate into DNA molecules (Fig. 5-23 Box 28-A). There is no single mode of action. The search for suitable antibiotics for human use consists in finding compounds highly toxic to infective organisms but with low toxicity to human cells. 

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... 

A. Accumulation of tetracyclines by susceptible organisms is mediated by transport proteins located in the bacterial membrane. 

Tetracycline Binds to the 30S ribosomal subunit and prevents the tRNA from interacting with the ribosome A membrane protein actively expels or transports the antibiotic out of the cell... 

Tetracyclines Porins (especially OmpF) Energy-independent (passive) and energy-dependent (active) transport systems... 

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]. 

Altered transport Efflux Reduced Uptake Tetracycline, Fluoroquinolones Aminoglycosides, Chloramphenicol... 

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). 

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