RESISTANCE TO TETRACYCLINE ANTIBIOTICS

Tetracyclines (tetracycline, doxycycline, minocycline, oxtetracycline, ...) are antibiotics which inhibit the bacterial growth by stopping protein synthesis. They have been widely used for the past forty years as therapeutic agent in human and veterinary medicine but also as growth promotor in animal husbandry. The emergence of bacterial resistances to these antibiotics has nowadays limited their use. Three different specific mechanisms of tetracycline resistance have been identified so far: tetracycline efflux, ribosome protection and tetracycline modification.

Tetracycline efflux is achieved by an export protein from the major facilitator superfamily (MFS). The export protein was shown to function as an electroneutral antiport system which catalyzes the exchange of tetracycline-divalent-metal-cation complex for a proton. In Gram-negative bacteria the export protein contains 12 TMS (transmembrane fragments) whereas in Gram-positive bacteria it displays 14 TMS. Ribosome protection is mediated by a soluble protein which shares homolgy with the GTPases participating in protein synthesis, namely EF-Tu and EF-G. The third mechanism involves a cytoplasmic protein that chemically modifies tetracycline. This reaction takes only place in the presence of oxygen and NADPH and does not function in the natural host (Bacteroides). 

The two first mechanisms are the most widespread and most of their genes are normally acquired via transferable plasmids and/or transposons. These two mechanisms were observed both in aerobic and anaerobic Gram-negative or Gram-positive bacteria demonstrating their wide distribution among the bacterial kingdom. To date, about sixty-one tetracycline resistance genes have been sequenced and thirty-two classes of genes identified in non-producers and producers (Streptomyces). Each new class is identified by its inability to hybridize with any of the known tet genes under stringent conditions (Levy et al. 1989. AAC 33:1373-1374). A new nomenclature for the resistance determinants has been proposed for the future with the S. B. Levy group to coordinate the naming of the detreminants (Levy et al. 1999. AAC 43:1523-1524).