Molecular Paleontology Meets Drug Discovery: The Case for De-Extinct Antimicrobials

The rise of antibiotic resistance has necessitated the exploration of unconventional sources for novel antimicrobial agents. One emerging novel frontier is "de-extinct" molecules – bioactive peptides, antibiotics, and other bioactive agents reconstructed from ancient or extinct organisms – a groundbreaking convergence of paleogenomics, paleoproteomics, and synthetic biology. Recent advances in high-throughput DNA sequencing, mass spectrometry, and computational biology have enabled scientists to recover and analyze genetic and protein sequences from long-extinct species, offering unprecedented insights into evolutionary biology and potential applications in medicine, biotechnology, and conservation, including the successful reviving of antimicrobial molecules from several extinct organisms. While paleogenomics provides the blueprint for reconstructing extinct genomes, paleoproteomics offers complementary insights into gene expression, protein function, and post-translational modifications that are often lost in DNA-based studies. These approaches can yield proteins and metabolites that have been lost to evolution, offering a new reservoir of bioactive compounds that could revolutionize medicine, biotechnology, and synthetic biology. In this report we explore data from the CAS Content Collection to outline current landscape and research progress in the emerging area of molecular de-extinction, to identify key developing concepts and challenges and successfully revived de-extinct antimicrobials. We outline the technical approaches to their revival, in effort to understand how this highly innovative strategy helps combating modern multidrug-resistant pathogens, as well as the challenges and ethical considerations in deploying ancient molecules.