Ageitos Lucía, Boaro Andreia, Cesaro Angela, Torres Marcelo D T, Broset Esther, de la Fuente-Nunez Cesar
Machine Biology Group, Departments of Psychiatry and Microbiology, Institute for Biomedical Informatics, Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Departments of Bioengineering and Chemical and Biomolecular Engineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA, USA; Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, USA; Penn Institute for Computational Science, University of Pennsylvania, Philadelphia, PA, USA.
Machine Biology Group, Departments of Psychiatry and Microbiology, Institute for Biomedical Informatics, Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Departments of Bioengineering and Chemical and Biomolecular Engineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA, USA; Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, USA; Penn Institute for Computational Science, University of Pennsylvania, Philadelphia, PA, USA.
Trends Biotechnol. 2025 Jul;43(7):1642-1667. doi: 10.1016/j.tibtech.2025.02.007. Epub 2025 Mar 25.
Novel antibiotics are urgently needed since bacteria are becoming increasingly resistant to existing antimicrobial drugs. Furthermore, available antibiotics are broad spectrum, often causing off-target effects on host cells and the beneficial microbiome. To overcome these limitations, we used structure-guided design to generate synthetic peptides derived from Andersonin-D1, an antimicrobial peptide (AMP) produced by the odorous frog Odorrana andersonii. We found that both hydrophobicity and net charge were critical for its bioactivity, enabling the design of novel, optimized synthetic peptides. These peptides selectively targeted Gram-negative pathogens in single cultures and complex microbial consortia, showed no off-target effects on human cells or beneficial gut microbes, and did not select for bacterial resistance. Notably, they also exhibited in vivo activity in two preclinical murine models. Overall, we present synthetic peptides that selectively target pathogenic infections and offer promising preclinical antibiotic candidates.
由于细菌对现有抗菌药物的耐药性日益增强，新型抗生素亟待研发。此外，现有的抗生素多为广谱抗生素，常常会对宿主细胞和有益微生物群产生脱靶效应。为克服这些局限性，我们采用结构导向设计，从臭蛙（Odorrana andersonii）产生的抗菌肽Andersonin-D1衍生出合成肽。我们发现，疏水性和净电荷对其生物活性至关重要，这使得新型优化合成肽的设计成为可能。这些肽在单一培养物和复杂微生物群落中能选择性地靶向革兰氏阴性病原体，对人类细胞或有益肠道微生物无脱靶效应，也不会导致细菌产生耐药性。值得注意的是，它们在两种临床前小鼠模型中也表现出体内活性。总体而言，我们展示了能选择性靶向致病性感染的合成肽，并提供了有前景的临床前抗生素候选物。
