Infections by intracellular pathogens are difficult to treat because of the poor accessibility of antibiotics to the pathogens encased by host cell membranes. As such, a strategy that can improve the membrane permeability of antibiotics would significantly increase their efficiency against the intracellular pathogens. Here, we report the design of an adaptive, metaphilic cell-penetrating polypeptide (CPP)–antibiotic conjugate (VPP-G) that can effectively eradicate the intracellular bacteria both in vitro and in vivo. VPP-G was synthesized by attaching vancomycin to a highly membrane-penetrative guanidinium-functionalized metaphilic CPP. VPP-G effectively kills not only extracellular but also far more challenging intracellular pathogens, such as S. aureus, methicillin-resistant S. aureus, and vancomycin-resistant Enterococci. VPP-G enters the host cell via a unique metaphilic membrane penetration mechanism and kills intracellular bacteria through disruption of both cell wall biosynthesis and membrane integrity. This dual antimicrobial mechanism of VPP-G prevents bacteria from developing drug resistance and could also potentially kill dormant intracellular bacteria. VPP-G effectively eradicates MRSA in vivo, significantly outperforming vancomycin, which represents one of the most effective intracellular antibacterial agents reported so far. This strategy can be easily adapted to develop other conjugates against different intracellular pathogens by attaching different antibiotics to these highly membrane-penetrative metaphilic CPPs.

中文翻译：

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“间质性”细胞穿透多肽-万古霉素结合物通过双重机制有效根除细胞内细菌。

细胞内病原体的感染很难治疗，因为抗生素对宿主细胞膜包裹的病原体的可及性很差。这样，可以改善抗生素的膜通透性的策略将显着提高其对抗细胞内病原体的效率。这里，我们报告一个自适应，metaphilic细胞穿透肽（CPP）-antibiotic缀合物（VPP-G），可以有效地根除细胞内细菌两者的设计体外和体内。VPP-G是通过将万古霉素与高度渗透膜的胍基官能化的亲热CPP连接而合成的。VPP-G不仅可以杀死细胞外，而且可以杀死更具挑战性的细胞内病原体，例如金黄色葡萄球菌，耐甲氧西林的金黄色葡萄球菌和耐万古霉素的肠球菌。VPP-G通过独特的亲膜渗透机制进入宿主细胞，并通过破坏细胞壁生物合成和膜完整性杀死细胞内细菌。VPP-G的这种双重抗菌机制可防止细菌产生耐药性，还可能杀死潜在的细胞内细菌。VPP-G在体内有效消除MRSA明显优于万古霉素，后者是迄今为止报道的最有效的细胞内抗菌剂之一。通过将不同的抗生素附着到这些具有高膜渗透性的亲液性CPP上，可以轻松地使该策略适应于开发针对不同细胞内病原体的其他缀合物。