In vitro antibacterial activity of SM-7338, a carbapenem antibiotic with stability to dehydropeptidase I

Abstract

SM-7338, a new carbapenem antibiotic, was demonstrated to have potent antibacterial activity against a broad spectrum of aerobes, including Staphylococcus aureus, beta-hemolytic streptococci, Streptococcus pneumoniae, Haemophilus influenzae, Neisseria spp., members of the family Enterobacternaceae, Pseudomonas spp., and gram-positive and gram-negative anaerobes in a collection of 1,102 unselected clinical isolates. At a concentration of 0.5 ,Lg/ml, SM-7338 inhibited 90% of these strains. The spectkrum of activity of ceftazidiine and cefotaxime was more limited, and many of the Enterobacteriaceae and Pseudomonas spp. were resistant to these agentsv, piperacillin, or gentamncin. A collection of ofloxacin-resistant strains was inhibited by or imipenem at 4 ,ug/ml. SM-7338 was more active than metronidazole and clindamycin against anaerobes. Of the carbapenems, inipenem had greater activity against staphylococci, but SM-7338 was much more active against Haemophius, BranhameUa, and Neisseria spp. and all genera of Enterobacteriaceae tested. The MIC of SM-7338 for 90% of these strains ranged from <0.008 to 0.13 ,ug/ml. When tested against 124 strains of Pseudomonas aeruginosa, SM-7338 inhibited 76% at 0.5 ,ug/ml but imipenem inhibited only 15% at this concentration. Both carbapenems exhibited similar activities against Bacteroides spp., but SM-7338 was more active than hinipenem against Clostridium spp. The MBC of SM-7338 was most commonly the same as or twice the MIC. SM-7338 and imipenem showed excellent activities against bacteria elaborating chromosome-or plasmid-mediated ,B-lactamases, including those conferring resistance to broad-spectrum cephalosporins. The activity of SM-7338 was generally unaffected by the culture nmedium used, pH, 25% human serum, and inoculum size, but the susceptibility of Xanthomonas maltophilia was medium dependent.

Syntheses of Carnosic Acid and Carnosol, Anti-oxidants in Rosemary, from Pisiferic Acid, the Major Constituent of Sawara

“…Biological Activities Minimun inhibitory concentration (MIC mg/ml) of the synthetic carnosic acid 2 and carnosol 3 were measured against Propionibacterium acnes (ATCC 6919) 18) and Staphylococcus aureus ME/GM/TC Resistant (ATCC 33592) 19) to show the potential of these compounds as antibacterial drugs. Both of the synthetic compounds showed potent antibacterial activities against P. acnes and S. aureus ( Table 1).…”

“…Methods of Anti-microbial Activities in vitro Assays Minimun inhibitory concentration (MIC mg/ml) of the synthetic carnosic acid 2 and carnosol 3 were performed under conditions described in the literatures for each assay against Propionibacterium acnes (ATCC 6919) 18) and Staphylococcus aureus ME/GM/TC Resistant (ATCC 33592). 19) Two compounds 2 and 3 were tested at half-log concentrations ranging from 0.03 to 100 mg/ml in the P. acnes and S. aureus in vitro growth inhibition assays.…”

Stability of New Carbapenem DA-1131 to Renal Dipeptidase (Dehydropeptidase I)

“…Cilastatin, Z-2-(2,2-dimethylcyclopropanecarboxamido)-2-butenoic acid, is a specific competitive inhibitor of RDPase and is well matched in its pharmacokinetic properties for coadministration with imipenem (8,22). Therefore, imipenem is designed to be coadministered with cilastatin to suppress RDPase for its clinical use, and they are now manufactured in a 1:1 combination.Meropenemhept-2-ene-2-carboxylic acid, which was introduced in the late 1980s, though relatively less active against gram-positive bacteria than imipenem (1,4,6,7), is stable in the presence of RDPase as judged by its V max /K m ratio. Thus, it is currently in clinical use without coadministration of an RDPase inhibitor.…”

Antimicrobial activity of SM-17466, a novel carbapenem antibiotic with potent activity against methicillin-resistant Staphylococcus aureus

“…Imipenem was the first carbapenem antibiotic used clinically. Subsequently, many carbapenems, such as panipenem (RS-533) (5,14), meropenem (3,19), biapenem (L-627) (2,22,24), and BO-2727 (13) have been developed and used for the treatment of severe infections or in clinical trials. The emergence of, and now the epidemic nature, of methicillin-resistant Staphylococcus aureus is a serious problem in antibacterial chemotherapy (23).…”

“…In the process of research for new carbapenem compounds with activity against methicillin-resistant S. aureus, we synthesized a new 1␤-methyl carbapenem, SM-17466, (4R,5S,6S)-3-{[4-(1-aminocarbonyl-methyl-pyridino-4-yl)thiazol-2-yl]thio}-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3,2,0] hept-2-ene-2-carboxylate (Fig. 1).…”