Recent Developments in Tetracycline Antibiotics

Abstract: The rapid emergence of pathogenic bacteria resistant to tetracyclines and other currently available antibiotics has caused serious concern among medical professionals. It has heightened resurgent interest in studying 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 recent progress on elucidating the mechanisms of resistance, and the development of novel tet­ racyclines to combat bacterial resistance. Most of the new tetracycline derivatives described in this review have been either prepared semisynthetically or isolated from entation. In the semisynthetic area, efflux inhibitors that are effective in an in vitro model have been identified. A new class of tetracyclines, named glycylcyclines 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 compounds show potent activity against a broad spectrum of Gram-positive and Gram-negative bacteria, including strains that carry the two major tetracycline­ resistance determinants, efflux and ribosomal protection. Two of the glycylcycline derivatives, DMG-MINO and DMG-DMDOT, have been studied by several groups of investigators against a large number of clinical pathogens isolated from various sources. The spectrum of activity of these compounds includes organisms with resistance to antibiotics other than tetracyclines, e.g., methicillin-resistant staphylococci, penicillin-resistant streptococcus pneumoniae, and vancomycin-resistant enterococci. Their in vitro, as well as in vivo activity against bacteria with characterized tetracycline- or minocycline-resistant elements will be summarized. The structure-activity relationships of glycylcyclines and their mode of action will also be discussed.