Guignard Bertrand, Entenza José M, Moreillon Philippe
University of Lausanne, Department of Fundamental Microbiology, Biology Building, 1015 Lausanne, Switzerland.
Curr Opin Pharmacol. 2005 Oct;5(5):479-89. doi: 10.1016/j.coph.2005.06.002.
Methicillin-resistant Staphylococcus aureus (MRSA) have developed resistance to virtually all non-experimental antibiotics. They are intrinsically resistant to beta-lactams by virtue of newly acquired low-affinity penicillin-binding protein 2A (PBP2A). Because PBP2A can build the wall when other PBPs are blocked by beta-lactams, designing beta-lactams capable of blocking this additional target should help solve the issue. Older molecules including penicillin G, amoxicillin and ampicillin had relatively good PBP2A affinities, and successfully treated experimental endocarditis caused by MRSA, provided that the bacterial penicillinase could be inhibited. Newer anti-PBP2A beta-lactams with over 10-fold greater PBP2A affinities and low minimal inhibitory concentrations were developed, primarily in the cephem and carbapenem classes. They are also very resistant to penicillinase. Most have demonstrated anti-MRSA activity in animal models of infection, and two--the carbapenem CS-023 and the cephalosporin ceftopibrole medocaril--have proceeded to Phase II and Phase III clinical evaluation. Thus, clinically useful anti-MRSA beta-lactams are imminent.
耐甲氧西林金黄色葡萄球菌（MRSA）已对几乎所有非实验性抗生素产生耐药性。由于新获得的低亲和力青霉素结合蛋白2A（PBP2A），它们对β-内酰胺类药物具有内在耐药性。因为当其他青霉素结合蛋白被β-内酰胺类药物阻断时，PBP2A能够构建细胞壁，所以设计能够阻断这个额外靶点的β-内酰胺类药物应该有助于解决这个问题。包括青霉素G、阿莫西林和氨苄西林在内的老一代分子对PBP2A具有相对较好的亲和力，并且只要细菌青霉素酶能够被抑制，就能成功治疗由MRSA引起的实验性心内膜炎。主要在头孢菌素类和碳青霉烯类中开发出了对PBP2A亲和力超过10倍且最低抑菌浓度较低的新型抗PBP2Aβ-内酰胺类药物。它们对青霉素酶也具有很强的耐药性。大多数在感染动物模型中已显示出抗MRSA活性，其中两种——碳青霉烯类药物CS-023和头孢菌素类药物头孢托罗培南甲酯——已进入II期和III期临床评估。因此，临床上有用的抗MRSAβ-内酰胺类药物即将问世。
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