IN-VITRO AND IN-VIVO ANTIBACTERIAL ACTIVITIES OF THE GLYCYLCYCLINES, A NEW CLASS OF SEMISYNTHETIC TETRACYCLINES

N,N-Dimethylglycylamido (DMG) derivatives of minocycline and 6-demethy l-6-deoxytetracycline are new semisynthetic tetracyclines referred to as the glycylcyclines. The in vitro activities of the glycylcyclines w ere evaluated in comparison with those of minocycline and tetracycline against strains carrying characterized tetracycline resistance determ inants and against 995 recent clinical isolates obtained from geograph ically distinct medical centers in North America. The glycylcyclines w ere active against tetracycline-resistant strains carrying efflux [tet (A), tet(B), tet(C), and tet(D) in Escherichia coli and tet(K) in Stap hylococcus aureus] and ribosomal protection [tet(M) in S. aureus, Ente rococcus faecalis, and E. coli)] resistance determinants. Potent activ ity (MIC for 90% of strains, less-than-or-equal-to 0.5 mug/ml) was obt ained with the glycylcyclines against methicillin-susceptible and meth icillin-resistant S. aureus, E. faecalis, Enterococcus faecium, and va rious streptococcal species. The glycylcyclines exhibited good activit y against a wide diversity of gram-negative aerobic and anaerobic bact eria, most of which were less susceptible to minocycline and tetracycl ine. The activities of the glycylcyclines against most organisms teste d were comparable to each other. The in vivo efficacies of the glycylc yclines against acute lethal infections in mice when dosed intravenous ly were reflective of their in vitro activities. The glycylcyclines ha d efficacies comparable to that of minocycline against infections with methicillin-susceptible and methicillin-resistant S. aureus strains, a strain carrying tet(K), and a tetracycline-susceptible E. coli strai n but exceeded the effectiveness of minocycline against infections wit h resistant isolates, including strains harboring tet(M) or tet(B). Le vels of DMG-6-demethyl-6-deoxytetracycline in serum were higher and mo re sustained than those of DMG-minocycline or minocycline. Our results show that the glycylcyclines have potent in vitro activities against a wide spectrum of gram-positive and gram-negative, aerobic and anaero bic bacteria, including many resistant strains. On the basis of their in vitro and in vivo activities, the glycylcyclines represent a signif icant advance to the tetracycline class of antibiotics and have good p otential value for clinical efficacy.