Synergism between a Novel Chimeric Lysin and Oxacillin Protects against Infection by Methicillin-Resistant Staphylococcus aureus
Synergism between a Novel Chimeric Lysin and Oxacillin Protects against Infection by Methicillin-Resistant Staphylococcus aureus
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DOI：
10.1128/aac.01625-09
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发表时间：
2010-04-01
影响因子：
4.9
通讯作者：
Fischetti, Vincent A.
中科院分区：
文献类型：
--
作者：
Daniel, Anu;Euler, Chad;Fischetti, Vincent A.
金黄色葡萄球菌是几种严重传染病的病原体。耐抗生素金黄色葡萄球菌菌株的出现导致了严重的治疗困难，加剧了对新抗菌药物的需求。为此，我们开发了一种新型嵌合噬菌体（噬菌体）溶素，它对葡萄球菌具有活性，包括耐甲氧西林金黄色葡萄球菌（MRSA）。嵌合溶素（称为 ClyS）是通过将金黄色葡萄球菌 Twort 噬菌体溶素的 N 端催化结构域与另一种金黄色葡萄球菌噬菌体溶素 (phiNM3) 的 C 端细胞壁靶向结构域融合而获得的，该结构域显示出葡萄球菌特异性结合。 ClyS在大肠杆菌中表达，纯化的蛋白在体外裂解MRSA、万古霉素中间菌株（VISA）和甲氧西林敏感菌株（MSSA）金黄色葡萄球菌。在小鼠鼻腔去定植模型中，单次 ClyS 治疗 1 小时后，MRSA 细胞的活力下降了 2 个对数。在小鼠败血症模型中，腹腔注射一剂 ClyS 也能防止 MRSA 导致死亡。 ClyS 在体外表现出与万古霉素和苯唑西林协同相互作用的典型模式。更重要的是，在小鼠模型中，ClyS 和苯唑西林在单独没有保护作用的剂量下可以协同防止 MRSA 败血性死亡。这些结果有力地支持了 ClyS 的开发，作为当前多重耐药金黄色葡萄球菌感染治疗选择的一个有吸引力的补充，并将允许恢复因耐药性不断增加而被搁置的抗生素。
Staphylococcus aureus is the causative agent of several serious infectious diseases. The emergence of antibiotic-resistant S. aureus strains has resulted in significant treatment difficulties, intensifying the need for new antimicrobial agents. Toward this end, we have developed a novel chimeric bacteriophage (phage) lysin that is active against staphylococci, including methicillin-resistant S. aureus (MRSA). The chimeric lysin (called ClyS) was obtained by fusing the N-terminal catalytic domain of the S. aureus Twort phage lysin with the C-terminal cell wall-targeting domain from another S. aureus phage lysin (phiNM3), which displayed Staphylococcus-specific binding. ClyS was expressed in Escherichia coli, and the purified protein lysed MRSA, vancomycin-intermediate strains of S. aureus (VISA), and methicillin-sensitive (MSSA) strains of S. aureus in vitro. In a mouse nasal decolonization model, a 2-log reduction in the viability of MRSA cells was seen 1 h following a single treatment with ClyS. One intraperitoneal dose of ClyS also protected against death by MRSA in a mouse septicemia model. ClyS showed a typical pattern of synergistic interactions with both vancomycin and oxacillin in vitro. More importantly, ClyS and oxacillin at doses that were not protective individually protected synergistically against MRSA septic death in a mouse model. These results strongly support the development of ClyS as an attractive addition to the current treatment options of multidrug-resistant S. aureus infections and would allow for the reinstatement of antibiotics shelved because of mounting resistance.