Resistance to tetracyclines is widespread, likely resulting from widespread historical use, particularly in non-clinical (i.e. agricultural) applications. This has limited their clinical usefulness, especially against Enterobacteriaceae. There are several major mechanisms by which bacteria express resistance to antimicrobials, including the tetracyclines: target modification via ribosomal protection proteins, reduction of drug uptake, efflux pump systems, and enzyme inactivation. The first two are by far the most important.
Target modification. Bacterial cells can mitigate the effects of tetracyclines by using ribosomal protection proteins (RPPs). There are several genes that code for RPPs, but the most well-studied are Tet(M) and Tet(O). These are distributed widely in gram positive organisms, though seen in a few of the more fastidious gram negatives as well.(7) Structurally, RPPs are soluble proteins in the cytoplasm that resemble the elongation factors that normally assist in protein synthesis (e.g. EF-Tu). Mechanistically, they exert their effect by causing the tetracyclines to dissociate from their binding with the ribosome, possibly through an allosteric mechanism.(8) The aminoacyl-tRNA complexes can then once again bind to the ribosomal acceptor site, and protein synthesis can continue.
Efflux pumps. Of the resistance genes to the tetracyclines, efflux proteins have the greatest variability: there are a host of different efflux pump proteins, most denoted by Tet. All of these are membrane bound proteins that bind molecules of tetracyclines that have entered the cell, and transporting them back outside the cell using a proton gradient. Tetracycline efflux proteins have been divided into six groups based on protein sequence identity: Groups 1 and 2 are by far the most important. Group 1 includes Tet(A), Tet(B), Tet(C), etc. and are mostly found in gram negative organisms, with a wide distribution. Group 2, on the other hand, consists of Tet(K) and Tet(L), and are found in many gram positive bacteria.(7)
Tet(B) is particularly important as it is widespread especially among the Enterobacteriaceae, and is able to confer resistance to all the tetracyclines, including minocycline, whereas most of the other efflux proteins are not able to transport minocycline.(9) Additionally, while the wild type is not active against the glycylcyclines (i.e. tigecycline), there have been reported mutations in Tet(B), as well as in Tet(A), that extend the activity to this drug as well.(10)
Reduction of drug uptake. Reduction of drug uptake occurs primarily in gram negative bacteria via reduction in the concentration of porins that normally transport tetracyclines across the outer membrane. This may be achieved by any number or combination of mutations.(11) Additionally, the marR regulon has been reported to decrease OmpF production (as well as expression of efflux pump systems), and this can confer resistance to the tetracyclines as well as to other drug classes.(12)
Enzyme inactivation. The sole described system for enzymatic inactivation of tetracyclines is named Tet(X), and has only ever been found in Bacteroides fragilis.(7) It encodes an enzyme similar to NADPH oxidoreductases, requiring both NADPH and oxygen to be effective. Consequently, it has only ever been observed to confer resistance to the tetracyclines when cloned into E. coli, which can grow in aerobic, oxygenated environments.(13) The strict anaerobic growth requirements of B. fragilis coupled with the oxygen requirements of this enzyme make it unclear whether this gene is actually active in tetracycline resistance.(1)