Efficacy of Artilysin Art-175 against Resistant and Persistent Acinetobacter baumannii
Efficacy of Artilysin Art-175 against Resistant and Persistent Acinetobacter baumannii
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DOI：
10.1128/aac.00285-16
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发表时间：
2016-06-01
影响因子：
4.9
通讯作者：
Briers, Yves
中科院分区：
文献类型：
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作者：
Defraine, Valerie;Schuermans, Joris;Briers, Yves
噬菌体编码的内溶素已显示出作为一类具有独特作用模式的新型抗菌剂的前景。例如，肽聚糖降解。然而，革兰氏阴性病原体由于具有保护性外膜，通常不易受影响。 Artilysins 克服了这一障碍。 Artilysins 是选定的细胞内溶素与特定的外膜不稳定肽的优化、工程融合物。 Artilysin Art-175 包含细胞内溶素 KZ144 的修饰变体，其 N 端与 SMAP-29 融合。此前，我们已经证明铜绿假单胞菌对 Art-175 具有高度敏感性。在此，我们报道 Art-175 对多重耐药鲍曼不动杆菌的稳定期细胞具有高度杀菌作用，甚至可以完全消除大接种量 (>= 10(8) CFU/ml)。除了活跃分裂的细胞外，Art-175 还会杀死持续细胞。将细菌固定在微流体流动池中后，可以观察到鲍曼不动杆菌与 Art-175 接触后立即被杀死。肽聚糖降解后通过渗透裂解来有效杀死细胞。添加 0.5 mM EDTA 可提高杀灭率。在选择压力下没有观察到对Art-175的抗性的发展，并且没有观察到与现有抗性机制的交叉抗性。总之，Art-175 代表了一种高活性 Artilysin，可对抗鲍曼不动杆菌和铜绿假单胞菌（假单胞菌目中两种最致命的病原体）。
Bacteriophage-encoded endolysins have shown promise as a novel class of antibacterials with a unique mode of action, i. e., peptidoglycan degradation. However, Gram-negative pathogens are generally not susceptible due to their protective outer membrane. Artilysins overcome this barrier. Artilysins are optimized, engineered fusions of selected endolysins with specific outer membrane-destabilizing peptides. Artilysin Art-175 comprises a modified variant of endolysin KZ144 with an N-terminal fusion to SMAP-29. Previously, we have shown the high susceptibility of Pseudomonas aeruginosa to Art-175. Here, we report that Art-175 is highly bactericidal against stationary-phase cells of multidrug-resistant Acinetobacter baumannii, even resulting in a complete elimination of large inocula (>= 10(8) CFU/ml). Besides actively dividing cells, Art-175 also kills persisters. Instantaneous killing of A. baumannii upon contact with Art-175 could be visualized after immobilization of the bacteria in a microfluidic flow cell. Effective killing of a cell takes place through osmotic lysis after peptidoglycan degradation. The killing rate is enhanced by the addition of 0.5 mM EDTA. No development of resistance to Art-175 under selection pressure and no cross-resistance with existing resistance mechanisms could be observed. In conclusion, Art-175 represents a highly active Artilysin against both A. baumannii and P. aeruginosa, two of the most life-threatening pathogens of the order Pseudomonadales.