RECENT DEVELOPMENTS IN TETRACYCLINE ANTIBIOTICS

The rapid emergence of pathogenic bacteria resistant to tetracyclines and other currently available antibiotics has caused serious concern a mong medical professionals. It has heightened resurgent interest in st udying the mechanisms of resistance and in developing new antibiotics. A comprehensive review has outlined the developments of tetracyclines prior to 1980 [47]. This review will highlight the pertinent advances in the tetracycline field during the last two decades, including rece nt progress on elucidating the mechanisms of resistance, and the devel opment of novel tetracyclines to combat bacterial resistance. Most of the new tetracycline derivatives described in this review have been ei ther prepared semisynthetically or isolated from fermentation. In the semisynthetic area, efflux inhibitors that are effective in an in vitr o model have been identified. A new class of tetracyclines, named glyc ylcyclines, has been the subject of numerous reports, and will be the major focus of this review. The glycylcyclines are currently the only derivatives that exhibit antibacterial activity comparable to that of the early tetracyclines when they were first introduced. These compoun ds show potent activity against a broad spectrum of Gram-positive and Gram-negative bacteria, including strains that carry the two major tet racycline-resistance determinants, efflux and ribosomal protection. Tw o of the glycylcycline derivatives, DMG-MINO and DMG-DMDOT, have been studied by several groups of investigators against a large number of c linical pathogens isolated from various sources. The spectrum of activ ity of these compounds includes organisms with resistance to antibioti cs other than tetracyclines, e.g., methicillin-resistant staphylococci , penicillin-resistant streptococcus pneumoniae, and vancomycin-resist ant enterococci. Their in vitro, as well as in vivo activity against b acteria with characterized tetracycline- or minocycline-resistant elem ents will be summarized. The structure-activity relationships of glycy lcyclines and their mode of action will also be discussed.