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E. coli can become resistant to tetracycline through several mechanisms, including the acquisition of resistance genes via horizontal gene transfer, the efflux of the antibiotic out of the cell, and modifications of the drug's target site. Tetracycline resistance genes often encode proteins that can pump the drug out of the bacterial cell or alter ribosomal targets, thereby diminishing the antibiotic's effectiveness. Additionally, the overuse and misuse of tetracycline in agriculture and medicine have accelerated the development of resistant strains.

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