Chimerophore antibiotics: engineered multimodal host defense peptides
Armas-Egas, L.; Lagler, S.; Panke, S.; Held, M.
Show abstract
Ribosomally synthesized host defense peptides (HDPs) are promising candidates for novel antibiotics. However, non-lytic HDPs, which target intracellular machinery, remain underexploited due to limitations including low potency in serum and narrow activity spectra. To enhance their therapeutic profile, we fused non-lytic HDPs generating "chimerophores" with multimodal mechanisms of action (MOAs). Using a high-throughput self-screening platform (Mex), we synthesized and evaluated a combinatorial library of 99,235 variants, identifying over 30,300 active chimerophores, vastly expanding the functional space of chimeric HDPs. Functional screening of 18 chimerophores revealed candidates with potent, broad-spectrum activity displaying serum-tolerance, low cytotoxicity, orthogonal uptake pathways and multimodality, such as simultaneously targeting of ribosomes and DNA. Integrating these distinct mechanisms into a single molecule allowed lead candidate cp9 to suppress the emergence of resistance in Pseudomonas aeruginosa, establishing a scalable platform for the systematic engineering of next-generation multimodal antibiotics.
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