Novel antibiotics are urgently needed to combat multidrug-resistant pathogens. Venoms represent previously untapped sources of novel drugs. Here we repurposed mastoparan-L, the toxic active principle derived from the venom of the wasp Vespula lewisii, into synthetic antimicrobials. We engineered within its N terminus a motif conserved among natural peptides with potent immunomodulatory and antimicrobial activities. The resulting peptide, mast-MO, adopted an α-helical structure as determined by NMR, exhibited increased antibacterial properties comparable to standard-of-care antibiotics both in vitro and in vivo, and potentiated the activity of different classes of antibiotics. Mechanism-of-action studies revealed that mast-MO targets bacteria by rapidly permeabilizing their outer membrane. In animal models, the peptide displayed direct antimicrobial activity, led to enhanced ability to attract leukocytes to the infection site, and was able to control inflammation. Permutation studies depleted the remaining toxicity of mast-MO toward human cells, yielding derivatives with antiinfective activity in animals. We demonstrate a rational design strategy for repurposing venoms into promising antimicrobials.

迫切需要新型抗生素来对抗具有多重耐药性的病原体。毒液代表以前未开发的新药来源。在这里，我们改用了马多巴兰-L（一种源自黄蜂黄蜂（Vaspula lewisii）毒液的有毒活性成分），制成合成抗菌剂。我们在其N末端设计了一个在自然肽中具有保守免疫力和抗微生物活性的保守基序。所得的肽，Mast-MO，采用NMR测得的α-螺旋结构，在体外和体内均表现出与护理标准抗生素相当的抗菌性能，并增强了不同种类抗生素的活性。作用机理研究表明，mast-MO通过快速渗透细菌的外膜来靶向细菌。在动物模型中，该肽表现出直接的抗菌活性，导致将白细胞吸引到感染部位的能力增强，并且能够控制炎症。排列研究消除了mast-MO对人体细胞的残留毒性，在动物体内产生具有抗感染活性的衍生物。我们展示了一种合理的设计策略，可将毒液重新转化为有前途的抗菌剂。