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Abstract The development of eukaryote‐derived antimicrobial peptides as systemically administered drugs has proven a challenging task. Here, we report the first human oral actinomyces‐sourced defensin—actinomycesin—that shows promise for systemic therapy. Actinomycesin and its homologs are only present in actinobacteria and myxobacteria, and share similarity with a group of ancient invertebrate‐type defensins reported in fungi and invertebrates. Signatures of natural selection were detected in defensins from the actinomyces colonized in human oral cavity and ruminant rumen and dental plaque, highlighting their role in adaptation to complex multispecies bacterial communities. Consistently, actinomycesin exhibited potent antibacterial activity against oral bacteria and clinical isolates of Staphylococcus and synergized with two classes of human salivary antibacterial factors. Actinomycesin specifically inhibited bacterial peptidoglycan synthesis and displayed weak immunomodulatory activity and low toxicity on human and mammalian cells and ion channels in the heart and central nervous system. Actinomycesin was highly efficient in mice infected with Streptococcus pneumoniae and mice with MRSA‐induced experimental peritoneal infection. This work identifies human oral bacteria as a new source of systemic anti‐infective drugs.

The development of eukaryote‐derived antimicrobial peptides as systemically administered drugs has proven a challenging task. Here, we report the first human oral actinomyces‐sourced defensin—actinomycesin—that shows promise for systemic therapy. Actinomycesin and its homologs are only present in actinobacteria and myxobacteria, and share similarity with a group of ancient invertebrate‐type defensins reported in fungi and invertebrates. Signatures of natural selection were detected in defensins from the actinomyces colonized in human oral cavity and ruminant rumen and dental plaque, highlighting their role in adaptation to complex multispecies bacterial communities. Consistently, actinomycesin exhibited potent antibacterial activity against oral bacteria and clinical isolates of Staphylococcus and synergized with two classes of human salivary antibacterial factors. Actinomycesin specifically inhibited bacterial peptidoglycan synthesis and displayed weak immunomodulatory activity and low toxicity on human and mammalian cells and ion channels in the heart and central nervous system. Actinomycesin was highly efficient in mice infected with Streptococcus pneumoniae and mice with MRSA‐induced experimental peritoneal infection. This work identifies human oral bacteria as a new source of systemic anti‐infective drugs. Synopsis: Bacteria are a major source of clinically used antibiotics. This study explored the potential of oral actinomyces‐sourced defensins as systemic anti‐infective drugs via a combination of microbial genome mining, evolution analysis and experimental studies. Bacterial defensins with the cysteine‐stabilized α‐helical and β‐sheet motif are exclusively present in actinomycetes and myxobacteria.AMSIN kills sensitive bacteria through interaction with Lipid II to hamper cell‐wall biosynthesis.AMSIN shows low toxicity and antibacterial activity in undiluted human serum, which is superior to some human‐derived host defense peptides. [ABSTRACT FROM AUTHOR]