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

Abstract

The in vitro and in vivo antibacterial activities of SM-17466, a new 1␤-methyl carbapenem, were evaluated against a wide range of clinical bacterial isolates and compared with the activities of meropenem, imipenem, vancomycin, and arbekacin. SM-17466 had a broad spectrum of action against gram-positive bacteria, showing especially potent activity against methicillin-resistant staphylococci. The MICs of SM-17466, meropenem, imipenem, vancomycin, and arbekacin at which 90% of clinical isolates of methicillin-resistant Staphylococcus aureus were inhibited were 3.13, 50, 100, 1.56, and 3.13 g/ml, respectively. This activity of SM-17466 was almost equivalent to those of the antibiotics used for the treatment of infections caused by this organism. SM-17466 also showed bactericidal activity against methicillin-resistant S. aureus. In contrast, SM-17466 was less active against gram-negative bacteria, especially against Pseudomonas aeruginosa, compared with the other carbapenems; however, of the carbapenems, SM-17466 exhibited the highest activity against Haemophilus influenzae and Bacteroides fragilis. SM-17466, at a 50% inhibitory concentration of less than 1 g/ml, bound to penicillin-binding proteins 1 to 4 in methicillin-susceptible S. aureus and also had good binding to penicillinbinding protein 2 in a methicillin-resistant strain (50% inhibitory concentration, 5.9 g/ml). This high affinity, which was 10 and 20 times greater than those for meropenem and imipenem, respectively, was reflected in the potent activity of SM-17466 against methicillin-resistant S. aureus. SM-17466 demonstrated excellent in vivo efficacy against methicillin-susceptible and -resistant S. aureus strains in a mouse peritoneal infection model: the efficacy of SM-17466 against methicillin-resistant strains was equal to or one-third that of vancomycin. This activity was comparable to the in vitro activity of SM-17466. The subcutaneous injection of SM-17466 in mice revealed that the half-life of SM-17466 in serum was about 18 min, intermediate between those of vancomycin and arbekacin and 1.5-fold that of imipenem-cilastatin. SM-17466 was resistant to hydrolysis by swine renal dehydropeptidase I, to an extent comparable to the resistance shown by meropenem.

PBP 2a Mutations Producing Very-High-Level Resistance to Beta-Lactams

“…The beta-lactam antibiotics that are used clinically do not bind to PBP 2a at therapeutic concentrations and therefore lack efficacy against infections caused by methicillin-resistant staphylococci. With the solution of the crystal structure of a soluble derivative of PBP 2a, low-affinity binding can be attributed at least in part to an energetically unfavorable acylation reaction of the active site serine due to the slippage of the beta-lactam molecule within a long groove that serves as the initial, reversible binding site in the formation of the Michaelis-Menten complex (16).Several cephalosporin and carbapenem derivatives that bind to PBP 2a with 100-fold or higher affinities than those of other beta-lactams and which are active in vitro and in vivo against methicillin-resistant staphylococci have been synthesized (2,6,7,13,20). These compounds have in common a relatively extended side chain attached to the ␣ ring of the beta-lactam compound core (3, 16).…”

The Management of Infection and Colonization due to Methicillin‐Resistant Staphylococcus aureus: A CIDS/CAMM Position Paper

“…Although drugs such as moxifloxacin, gatifloxacin and gemifloxacin have enhanced activity against staphylococci and MRSA (MIC 90 , 0.5 to 8.0 µg/mL) (55-58), there have been no published reports describing the use of these agents for the treatment of MRSA infections. Currently available fluoroquinolones are not recommended for the treatment of MRSA infections.…”

“…New carbapenems (eg, L-695,256 and SM-17466) able to bind to PBP 2a with a high degree of affinity have also been developed. These drugs appear to be active in vitro against MRSA strains (89,90) and L-695,256 appears to be as effective as vancomycin in an animal model of endocarditis (89).…”

New Anti-MRSA and Anti-VRE Carbapenems; Synthesis and Structure-activity Relationships of 1.BETA.-Metyl-2-(thiazol-2-ylthio)carbapenems.

“…Several problems, however, such as the spread of teicoplanin-and arbekacin-resistant MRSA4) and the current emergence of glycopeptideintermediate S. aureus (GISA)5) are certainly reducing the efficacy of these drugs in the clinic. VRE were first reported in 1986, and identified with increasing frequency in many nations over the past 10 years6 26). However, it was found that the activity against VREFm was insufficient to allow for useful in vivo efficacy.…”