Molecular de-extinction of ancient antimicrobial peptides enabled by machine learning.

Bibliographic Collection: 
Publication Type: Journal Article
Authors: Maasch, Jacqueline R M A; Torres, Marcelo D T; Melo, Marcelo C R; de la Fuente-Nunez, Cesar
Year of Publication: 2023
Journal: Cell Host Microbe
Volume: 31
Issue: 8
Pagination: 1260-1274.e6
Date Published: 2023 Aug 09
Publication Language: eng
ISSN: 1934-6069
Keywords: Animals, Anti-Bacterial Agents, Anti-Infective Agents, Antimicrobial Peptides, Humans, Machine Learning, Mice, Microbial Sensitivity Tests, Peptide Hydrolases, Peptides

Molecular de-extinction could offer avenues for drug discovery by reintroducing bioactive molecules that are no longer encoded by extant organisms. To prospect for antimicrobial peptides encrypted within extinct and extant human proteins, we introduce the panCleave random forest model for proteome-wide cleavage site prediction. Our model outperformed multiple protease-specific cleavage site classifiers for three modern human caspases, despite its pan-protease design. Antimicrobial activity was observed in vitro for modern and archaic protein fragments identified with panCleave. Lead peptides showed resistance to proteolysis and exhibited variable membrane permeabilization. Additionally, representative modern and archaic protein fragments showed anti-infective efficacy against A. baumannii in both a skin abscess infection model and a preclinical murine thigh infection model. These results suggest that machine-learning-based encrypted peptide prospection can identify stable, nontoxic peptide antibiotics. Moreover, we establish molecular de-extinction through paleoproteome mining as a framework for antibacterial drug discovery.

DOI: 10.1016/j.chom.2023.07.001
Alternate Journal: Cell Host Microbe