In vitro and in vivo antibacterial activities of a novel glycylcycline, the 9-t-butylglycylamido derivative of minocycline (GAR-936)

The 9-t-butylglycylamido derivative of minocycline (TBG-MINO) is a recently synthesized member of a novel group of antibiotics, the glycylcyclines, Th is new derivative, like the first glycylcyclines, the N,N-dimethylglycylami do derivative of minocycline and 6-demethyl-6-deoxytetracycline, possesses activity against bacterial isolates containing the two major determinants r esponsible for tetracycline resistance: ribosomal protection and active eff lux. The in vitro activities of TBG-MINO and the comparative agents were ev aluated against strains with characterized tetracycline resistance as well as a spectrum of recent clinical aerobic and anaerobic gram-positive and gr am-negative bacteria. TBG-MINO, with an MIC range of 0.25 to 0.5 mu g/ml, s howed good activity against strains expressing tet(M) (ribosomal protection ), fet(A), tet(B), tet(C), tet(D), and tet(K) (efflux resistance determinan ts), TBG-MINO exhibited similar activity against methicillin-resistant Stap hylococcus aureus (MRSA), penicillin-resistant streptococci, and vancomycin -resistant enterococci (MICs at which 90% of strains are inhibited, less th an or equal to 0.5 mu g/ml). TBG-MINO exhibited activity against a wide div ersity of gram-negative aerobic and anaerobic bacteria, most of which were less susceptible to tetracycline and minocycline, The in vivo protective ef fects of TBG-MINO were examined against acute lethal infections in mice cau sed by Escherichia coli, S. aureus, and Streptococcus pneumoniae isolates. TBG-MINO, administered intravenously, demonstrated efficacy against infecti ons caused by S, aureus including MRSA. strains and strains containing tet( K) or tct(M) resistance determinants (median effective doses [ED(50)s], 0.7 9 to 2.3 mg/kg of body weight), TBG-MINO demonstrated efficacy against infe ctions caused by tetracycline-sensitive E. coil strains as well as E. coil strains containing either et(M) or the efflux determinant tet(A), tet(B), o r tet(C) (ED(50)s, 1.5 to 3.5 mg/kg), Overall, TBG-MINO shows antibacterial activity against a wide spectrum of gram-positive and gram-negative aerobi c and anaerobic bacteria including strains resistant to other chemotherapeu tic agents. The in vivo protective effects, especially against infections c aused by resistant bacteria, corresponded with the in vitro activity of TBG -MINO.