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Antimicrobial Agents and Chemotherapy, February 2003, p. 658-664, Vol. 47, No. 2
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.2.658-664.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

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

Francois Malouin,{dagger} Johanne Blais, Suzanne Chamberland,{ddagger} Monica Hoang, Craig Park, Christin Chan, Kristina Mathias, Samia Hakem, Kelly Dupree, Eric Liu, Tien Nguyen, and Michael N. Dudley*

Essential Therapeutics, Inc., Mountain View, California 94043

Received 25 June 2002/ Returned for modification 24 September 2002/ Accepted 15 November 2002

RWJ-54428 (MC-02,479) is a new cephalosporin active against gram-positive bacteria, including methicillin-resistant 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 µg/ml) and also showed affinity for PBP 2a, with a 50% inhibitory concentration (IC50) of 0.7 µg/ml. RWJ-54428 also displayed excellent affinity for PBP 5 from Enterococcus hirae R40, with an IC50 of 0.8 µg/ml and a MIC of 0.5 µg/ml. The affinity of RWJ-54428 for PBPs of ß-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 ß-lactamase isolated from S. aureus PC1. In addition, RWJ-54428 displayed low MICs against strains of S. aureus bearing the four classes of staphylococcal ß-lactamases, including ß-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 ß-lactamase, properties that may explain our inability to find resistance by standard methods. These data are consistent with its excellent activity against ß-lactam-resistant gram-positive bacteria.

* Corresponding author. Mailing address: Essential Therapeutics, Inc., 850 Maude Ave., Mountain View, CA 94043. Phone: (650) 428-3571. Fax: (650) 428-3534. E-mail: mdudley{at}etrx.com.

{dagger} Present address: Université de Sherbrooke, Faculté des sciences, département de biologie and CEVDM, Sherbrooke, Québec, Canada J1K 2R1.

{ddagger} Present address: Ulysses Pharmaceuticals, Eastman, Québec, Canada J0E 1P0.

Antimicrobial Agents and Chemotherapy, February 2003, p. 658-664, Vol. 47, No. 2
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.2.658-664.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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