Antimicrobial peptides are important candidates for developing new classes of antibiotics because of their potency against antibiotic-resistant pathogens. Current research focuses on topical applications and it is unclear how to design peptides with systemic efficacy. To address this problem, we designed two potent peptides by combining database-guided discovery with structure-based design. When bound to membranes, these two short peptides with an identical amino acid composition can adopt two distinct amphipathic structures: A classic horizontal helix (horine) and a novel vertical spiral structure (verine). Their horizontal and vertical orientations on membranes were determined by solid-state ¹⁵N NMR data. While horine was potent primarily against gram-positive pathogens, verine showed broad-spectrum antimicrobial activity. Both peptides protected greater than 80% mice from infection-caused deaths. Moreover, horine and verine also displayed significant systemic efficacy in different murine models comparable to conventional antibiotics. In addition, they could eliminate resistant pathogens and preformed biofilms. Significantly, the peptides showed no nephrotoxicity to mice after intraperitoneal or intravenous administration for 1 wk. Our study underscores the significance of horine and verine in fighting drug-resistant pathogens.

抗菌肽因其对抗生素耐药性病原体的效力而成为开发新型抗生素的重要候选者。当前的研究集中在局部应用上，尚不清楚如何设计具有全身功效的肽。为了解决这个问题，我们通过结合数据库指导的发现与基于结构的设计来设计了两种有效的肽。当与膜结合时，这两个具有相同氨基酸组成的短肽可以采用两种截然不同的两亲结构：经典的水平螺旋（马）和新颖的垂直螺旋结构（马林）。它们在膜上的水平和垂直方向由固态^15决定N NMR数据。虽然小便主要对革兰氏阳性病原体有效，但Verine具有广谱抗菌活性。两种肽均可保护超过80％的小鼠免于感染引起的死亡。此外，与常规抗生素相比，在不同的鼠模型中，尿液和Verine也显示出显着的全身功效。此外，它们还可以消除耐药菌和预先形成的生物膜。明显地，在腹膜内或静脉内给药1周后，该肽对小鼠没有显示出肾毒性。我们的研究强调了在抵抗耐药性病原体方面，荷尔蒙和维纳的重要性。