Functions of tetracycline efflux proteins that do not involve tetracycline

Tet(L) and Tet(K) are specific antibiotic-resistance determinants. They catalyze efflux of a tetracycline(Tc)-divalent metal complex in exchange for protons, as do other Tet efflux proteins. These Tet proteins also catalyze Na+ and K+ exchange for protons. Each of the "cytoplasmic substrates", Na+, K+ and the Tc-metal ion complex, can also be exchanged for K+, a catalytic mode that accounts for the long-recognized K+ uptake capacity conferred by some Tet proteins. The multiple catalytic modes of Tet(L) and Tet(K) provide potential new avenues for development of inhibitors of these efflux systems as well as avenues for exploration of structure-function relationships. The multiple catalytic modes of Tet(L), which is chromosomally encoded in Bacillus subtilis, also correspond to diverse physiological roles, including roles in antibiotic-, Na+-, and alkali-resistance as well as K+ acquisition. The use of K+ as an external coupling ion may contribute not only to the organism's K+ uptake capacity but also to its ability to exclude Na+ and Tc at elevated pH values. Regulation of the chromosomal tetL gene by Tc has been proposed to involve a translational re-initiation mechanism that is novel for an antibiotic-resistance gene and increases Tet expression seven-fold. Other elements of tetL expression and its regulation are already evident, including gene amplification and use of multiple promoters. However, further studies are required to clarify the full panoply of regulatory mechanisms, and their integration to ensure different levels of tetL expression that are optimal for its different functions. It will also be of interest to investigate the implications of Tet(L) and Tet(K) multifunctionality on the emergence and persistence of these antibiotic-resistance genes.