RWJ-54428 (MC-02,479), a new cephalosporin with high affinity for penicillin-binding proteins, including PBP 2a, and stability to staphylococcal beta-lactamases

被引：26

作者：

Malouin, F ^{[1
]}

Blais, J ^{[1
]}

Chamberland, S ^{[1
]}

Hoang, M ^{[1
]}

Park, C ^{[1
]}

Chan, C ^{[1
]}

Mathias, K ^{[1
]}

Hakem, S ^{[1
]}

Dupree, K ^{[1
]}

Liu, E ^{[1
]}

Nguyen, T ^{[1
]}

Dudley, MN ^{[1
]}

机构：

[1] Essential Therapeut Inc, Mt View, CA 94043 USA

来源：

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY | 2003年 / 47卷 / 02期

关键词：

D O I：

10.1128/AAC.47.2.658-664.2003

中图分类号：

Q93 [微生物学];

学科分类号：

071005 ; 100705 ;

摘要：

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

引用

页码：658 / 664

页数：7

共 42 条

[1] STUDIES ON THE CHEMICAL NATURE OF THE SUBSTANCE INDUCING TRANSFORMATION OF PNEUMOCOCCAL TYPES INDUCTION OF TRANSFORMATION BY A DESOXYRIBONUCLEIC ACID FRACTION ISOLATED FROM PNEUMOCOCCUS TYPE III [J].