Discovery and characterization of miranthins, “Trojan horse” antibiotic modulators of bacterial composition in the oral microbiome

Bacteria of the human microbiota encode an abundance of natural products that likely mediate bacterial competition, local colonization patterns, and human health and disease. However, very few of these compounds have been identified and characterized to date. During our investigation of Streptococcus mitis , an important early colonizer of the oral cavity, we identified and structurally characterized a family of peptide natural products, termed miranthins herein, that contain an unusual macrocycle formed by an Asp-Cys β-carbon thioether crosslink. We determined that the most abundantly secreted miranthin is a “Trojan horse” antibiotic that enters sensitive cells via the Ami oligopeptide transporter, is hydrolyzed and activated by aminopeptidase N, and subsequently inhibits ribosomal translation to curb the growth of streptococcal competitors. The miranthins are narrow-spectrum antibiotics that could enable S. mitis to modulate community dynamics in the oral cavity, highlighting the importance of peptide natural products in interspecies competition in the microbiome.