RWJ-54428 (MC-02,479), a New Cephalosporin with High Affinity for Penicillin-Binding Proteins, Including PBP 2a, and Stability to Staphylococcal Beta-Lactamases

Abstract

RWJ-54428 (MC-02,479) is a new cephalosporin active against gram-positive bacteria, including methicillinresistant Staphylococcus aureus (MRSA). The potency of this new cephalosporin against MRSA is related to a high affinity for penicillin-binding protein 2a (PBP 2a), as assessed in a competition assay using biotinylated ampicillin as the reporter molecule. RWJ-54428 had high activity against MRSA strains COL and 67-0 (MIC of 1 g/ml) and also showed affinity for PBP 2a, with a 50% inhibitory concentration (IC 50 ) of 0.7 g/ml. RWJ-54428 also displayed excellent affinity for PBP 5 from Enterococcus hirae R40, with an IC 50 of 0.8 g/ml and a MIC of 0.5 g/ml. The affinity of RWJ-54428 for PBPs of ␤-lactam-susceptible S. aureus (MSSA), enterococci (E. hirae), and Streptococcus pneumoniae showed that the good affinity of RWJ-54428 for MRSA PBP 2a and E. hirae PBP 5 does not compromise its binding to susceptible PBPs. RWJ-54428 showed stability to hydrolysis by purified type A ␤-lactamase isolated from S. aureus PC1. In addition, RWJ-54428 displayed low MICs against strains of S. aureus bearing the four classes of staphylococcal ␤-lactamases, including ␤-lactamase hyperproducers. The frequency of isolation of resistant mutants to RWJ-54428 from MRSA strains was very low. In summary, RWJ-54428 has high affinity to multiple PBPs and is stable to ␤-lactamase, properties that may explain our inability to find resistance by standard methods. These data are consistent with its excellent activity against ␤-lactam-resistant gram-positive bacteria.

Structure-Activity Relationships of Different β-Lactam Antibiotics against a Soluble Form of Enterococcus faecium PBP5, a Type II Bacterial Transpeptidase

“…Studies such as this complement the existing investigations that have used a similar approach to analyze the S. pneumoniae PBP2x and the methicillin-resistant PBP2a of S. aureus (10). Like investigations with ␤-lactamase inhibitors and the inactivation of inhibitor-resistant SHV enzymes, these data shows that both the affinity and rate at which ⌬1-36 rPBP is inactivated are significant factors in the evaluation of potent inhibitors of transpeptidation (7).…”

In Vivo Efficacy of Ceftaroline (PPI-0903), a New Broad-Spectrum Cephalosporin, Compared with Linezolid and Vancomycin against Methicillin-Resistant and Vancomycin-Intermediate Staphylococcus aureus in a Rabbit Endocarditis Model

“…Staphylococcus aureus is able to accumulate mechanisms of resistance to all clinically available compounds, including In the present circumstances, the search for new agents targeting the cell wall and, more specifically, the PBPs is a promising approach (4,10,16,17). The in vitro study of ceftaroline and comparison of the results with those obtained with the comparators confirmed the excellent activity of this new drug against MRSA strains.…”

Methicillin-Resistant Staphylococcus aureus: An Evolutionary, Epidemiologic, and Therapeutic Odyssey

“…The PBP2a affinity of BMS-247243 is 100-fold greater than that of methicillin or cefotaxime, and the drug is bactericidal against MRSA at twice the rate of vancomycin [112]. Other drugs of this class in development include the zwitterionic cephem RWJ-54428 [113], CB-181963 [114], BAL5788 [115], a prodrug of BAL9141 [116,117], and S-3578 [118]. ME1036 (formerly CP5609) is a C2-modified carbapenem with high affinity for PBP2a and with an MIC 90 of 2.0 mg/mL against MRSA [119].…”