Resistance to Tetracycline

Tetracycline binds to the 16S rRNA of the small subunit and also inhibits protein synthesis. However, the mechanism of resistance is quite different from chloramphenicol and aminoglycosides. Rather than inactivating tetracycline by modification, R-plasmids produce proteins that pump the antibiotic out of the bacteria. Tetracycline actually binds to both prokaryotic and eukaryotic ribosomes. Bacteria are more sensitive than animal cells because tetracyclines are actively taken up by bacterial cells, but not by eukaryotic cells. In fact, eukaryotic cells actively export tetracyclines. In tetracycline resistant bacteria, the antibiotic is actively taken into the cell, but then pumped out again. As there is no similarity between tetracycline and any known transportable nutrients, the purpose of the bacterial transport system that takes up tetracycline and its mechanism of operation are still baffling. However, the Tet resistance protein is part of a large family of sugar transporter proteins.

Plasmid-encoded tetracycline resistance is typically two level. A basal constitutive level of resistance protects by 5-10 fold relative to sensitive bacteria. In addition, exposure to tetracycline induces a second higher resistance level. Both resistance levels are due to production of proteins that are found in the cytoplasmic membrane and actively expel tetracycline from the cell. Tetracycline enters the cell as the protonated form by an active transport system. Inside the cell it binds Mg2+. The Tet resistance protein uses energy to expel the Tet-Mg2+ complex by proton antiport (Fig. 16.15).

neomycin phosphotransferase Enzyme that inactivates the antibiotics kanamycin and neomycin by adding a phosphate group npt gene Gene for neomycin phosphotransferase. Provides resistance against the antibiotics kanamycin and neomycin tetracycline Antibiotic that binds to 16S ribosomal RNA and inhibits protein synthesis

Tetracycline resistance protein

Tet-

FIGURE 16.15 Expulsion of Tetracycline from Resistant Bacteria

Tet-

-TetMg+

FIGURE 16.15 Expulsion of Tetracycline from Resistant Bacteria

The bacterial chromosome contains the gene for TetH, a protein that takes tetracycline from the environment and actively pumps the antibiotic and a proton into the cell. Once inside the cell, tetracycline complexes with Mg+, and may bind to the ribosome. In bacterial cells with an R-plasmid for tetracycline, another transport protein, called the tetracycline resistant protein, is manufactured. This protein allows a proton to enter the cell to produce energy for export of the Tet-Mg+ complex.

Resistance to trimethoprim and sulfonamides is due to replacement of the target enzyme.

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