Dual Targeting of Intracellular Pathogenic Bacteria with a Cleavable Conjugate of Kanamycin and an Antibacterial Cell-Penetrating Peptide.
Dual Targeting of Intracellular Pathogenic Bacteria with a Cleavable Conjugate of Kanamycin and an Antibacterial Cell-Penetrating Peptide.
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DOI：
10.1021/jacs.6b04831
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发表时间：
2016-08-31
影响因子：
15
通讯作者：
Chmielewski J
中科院分区：
文献类型：
--
作者：
Brezden A;Mohamed MF;Nepal M;Harwood JS;Kuriakose J;Seleem MN;Chmielewski J
由细胞内病原体引起的细菌感染，如分枝杆菌、沙门氏菌和布鲁氏菌，是一种迅速发展的全球卫生流行病，需要采取紧急行动。然而，一些抗生素，包括氨基糖苷类，对细胞内致病菌的治疗价值由于它们无法穿过真核生物膜而受到损害。为了解决这一重大问题，我们制备了抗生素卡那霉素的可切割偶联物和具有有效穿透哺乳动物细胞的非膜溶性广谱抗菌肽P14LRR。这种方法允许卡那霉素作为一种偶联物进入哺乳动物细胞，这种偶联物通过拴链连接，在细胞内的还原环境中分解。P14KanS偶联物的有效抗菌活性在体外被证明，这种可还原的偶联物比缺乏二硫段的偶联物更有效地清除巨噬细胞内的细胞内致病菌。值得注意的是，双抗生素偶联物成功清除了巨噬细胞内的结核分枝杆菌，并且在秀丽隐杆线虫模型中沙门氏菌水平显著降低。
Bacterial infection caused by intracellular pathogens, such as Mycobacterium, Salmonella, and Brucella, is a burgeoning global health epidemic that necessitates urgent action. However, the therapeutic value of a number of antibiotics, including aminoglycosides, against intracellular pathogenic bacteria is compromised due to their inability to traverse eukaryotic membranes. To address this significant problem, a cleavable conjugate of the antibiotic kanamycin and a non-membrane lytic, broad-spectrum antimicrobial peptide with efficient mammalian cell penetration, P14LRR, was prepared. This approach allows kanamycin to enter mammalian cells as a conjugate linked via a tether that breaks down in the reducing environment within cells. Potent antimicrobial activity of the P14KanS conjugate was demonstrated in vitro, and this reducible conjugate effectively cleared intracellular pathogenic bacteria within macrophage more potently than a conjugate lacking the disulfide moiety. Notably, successful clearance of Mycobacterium tuberculosis within macrophages was observed with the dual antibiotic conjugate, and Salmonella levels were significantly reduced in an in vivo Caenorhabditis elegans model.