SM-197436,
SM-232721, and
SM-232724 are new 1beta-methylcarbapenems with a unique 4-substituted thiazol-2-ylthio moiety at the C-2 side chain. In
agar dilution susceptibility testing these novel
carbapenems were active against methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis (MRSE) with a MIC(90) of </=4 micro g/ml. Furthermore,
SM-232724 showed strong bactericidal activity against MRSA, in contrast to
linezolid, which was bacteriostatic up to four times the MIC.
SM-232724 showed good therapeutic efficacy comparable to those of
vancomycin and
linezolid against systemic
infections of MRSA in
cyclophosphamide-treated mice. The MICs of
SM-197436,
SM-232721, and
SM-232724 for streptococci, including
penicillin-intermediate and
penicillin-resistant Streptococcus pneumoniae strains, ranged from </=0.063 to 0.5 micro g/ml. These drugs were the most active
beta-lactams tested against Enterococcus faecium, and the MIC(90) s for
ampicillin-resistant E. faecium ranged between 8 and 16 micro g/ml, which were slightly higher than the value for
linezolid. However, time-kill assays revealed the superior bactericidal activity of
SM-232724 compared to those of
quinupristin-dalfopristin and
linezolid against an E. faecium strain with a 4-log reduction in CFU at four times the MIC after 24 h of exposure to
antibiotics. In addition,
SM-232724 significantly reduced the numbers of bacteria in a murine
abscess model with the E. faecium strain: its efficacy was superior to that of
linezolid, although the MICs (2 micro g/ml) of these two agents are the same. Among gram-negative bacteria, these three
carbapenems were highly active against Haemophilus influenzae (including
ampicillin-resistant strains), Moraxella catarrhalis, and Bacteroides fragilis, and showed antibacterial activity equivalent to that of
imipenem for Escherichia coli, Klebsiella pneumoniae, and Proteus spp. Thus, these new
carbapenems are promising candidates for agents to treat nosocomial
bacterial infections by gram-positive and gram-negative bacteria, especially multiresistant gram-positive cocci, including MRSA and vancomycin-resistant enterococci.