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Engineered endolysin-based 'artilysins' to combat multidrug-resistant gram-negative pathogens

机译:基于内溶素的工程化“ artilysins”与多药耐药的革兰氏阴性病原体作斗争

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摘要

The global threat to public health posed by emerging multidrug-resistant bacteria in the past few years necessitates the development of novel approaches to combat bacterial infections. Endolysins encoded by bacterial viruses (or phages) represent one promising avenue of investigation. These enzyme-based antibacterials efficiently kill Gram-positive bacteria upon contact by specific cell wall hydrolysis. However, a major hurdle in their exploitation as antibacterials against Gram-negative pathogens is the impermeable lipopolysaccharide layer surrounding their cell wall. Therefore, we developed and optimized an approach to engineer these enzymes as outer membrane-penetrating endolysins (Artilysins), rendering them highly bactericidal against Gram-negative pathogens, including Pseudomonas aeruginosa and Acinetobacter baumannii. Artilysins combining a polycationic nonapeptide and a modular endolysin are able to kill these (multidrug-resistant) strains in vitro with a 4 to 5 log reduction within 30 min. We show that the activity of Artilysins can be further enhanced by the presence of a linker of increasing length between the peptide and endolysin or by a combination of both polycationic and hydrophobic/amphipathic peptides. Time-lapse microscopy confirmed the mode of action of polycationic Artilysins, showing that they pass the outer membrane to degrade the peptidoglycan with subsequent cell lysis. Artilysins are effective in vitro (human keratinocytes) and in vivo (Caenorhabditis elegans).
机译:在过去的几年中,新出现的耐多药细菌对全球公共卫生构成威胁,因此有必要开发新的方法来对抗细菌感染。由细菌病毒(或噬菌体)编码的内溶素代表了一种有希望的研究途径。这些基于酶的抗菌剂通过特定的细胞壁水解作用,可以有效地杀死革兰氏阳性细菌。然而,它们作为革兰氏阴性病原体的抗菌剂开发中的主要障碍是围绕其细胞壁的不可渗透的脂多糖层。因此,我们开发并优化了一种方法,将这些酶工程化为可穿透外膜的溶素(Artilysins),使其对革兰氏阴性病原菌(包括铜绿假单胞菌和鲍曼不动杆菌)具有高度的杀菌能力。溶血素结合了聚阳离子九肽和模块化的溶血素能够在30分钟内以4到5 log的减少量杀死这些菌株(耐多药)。我们显示,通过在肽和内溶素之间长度增加的连接子的存在或通过聚阳离子和疏水/两亲性肽的组合,可以进一步增强动脉溶素的活性。延时显微镜证实了聚阳离子溶血素的作用方式,表明它们通过外膜降解肽聚糖,随后细胞裂解。溶血素在体外(人角质形成细胞)和体内(秀丽隐杆线虫)均有效。

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