RWJ-54428 (MC-02,479), a new cephalosporin with high affinity for penicillin-binding proteins, including PBP 2a, and stability to staphylococcal beta-lactamases
RWJ-54428 (MC-02,479), a new cephalosporin with high affinity for penicillin-binding proteins, including PBP 2a, and stability to staphylococcal beta-lactamases
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DOI：
10.1128/aac.47.2.658-664.2003
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发表时间：
2003-02-01
影响因子：
4.9
通讯作者：
Dudley, MN
中科院分区：
文献类型：
--
作者：
Malouin, F;Blais, J;Dudley, MN
RWJ-54428（MC-02，479）是一种新的头孢菌素，对革兰氏阳性菌具有活性，包括耐甲氧西林金黄色葡萄球菌（MRSA）。这种新的头孢菌素对MRSA的效力与青霉素结合蛋白2a（PBP 2a）的高亲和力有关，如使用生物素化氨苄青霉素作为报告分子的竞争测定中所评估的。RWJ-54428对MRSA菌株COL和67-0具有高活性（MIC为1 μ g/ml），并且还显示对PBP 2a的亲和力，50%抑制浓度（IC 50）为0.7 μ g/ml。RWJ-54428对肠球菌R40的PBP 5也显示出极好的亲和力，IC 50为0.8 μ g/ml，MIC为0.5 μ g/ml。RWJ-54428对β-内酰胺敏感的S.金黄色葡萄球菌（MSSA）、肠球菌（E.对MRSA PBP 2a和E. histoprotein PBP 5不损害其与易感PBP的结合。RWJ-54428对从S. aureus PC1.此外，RWJ-54428对S.携带四类葡萄球菌β-内酰胺酶的金黄色葡萄球菌，包括β-内酰胺酶高产菌。从MRSA菌株中分离到对RWJ-54428耐药突变株的频率很低。总之，RWJ-54428对多种PBP具有高亲和力，并且对β-内酰胺酶稳定，这些特性可以解释我们无法通过标准方法发现耐药性。这些数据与其对β-内酰胺耐药革兰氏阳性菌的优异活性一致。
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.