Siamycin I

Siamycin I is a 21-residue tricyclic lasso peptide (RiPP) derived from Streptomyces that inhibits HIV-1 and HIV-2 fusion and viral replication by noncovalent interaction with the gp160 envelope glycoprotein, with resistance mapping to envelope mutations. Structural studies established a compact, amphipathic wedge-shaped conformation stabilized by disulfide bonds and an N-terminal macrolactam linkage. Beyond antiviral activity, siamycin I directly binds lipid II at the Gram-positive cell surface, compromising peptidoglycan biosynthesis and activating the liaI stress response. Additionally, it inhibits the histidine kinases FsrC and VanS, abolishing enterococcal virulence and restoring vancomycin susceptibility in resistant pathogens. These mechanistic findings define siamycin I as a multifunctional lasso peptide targeting viral envelope-mediated fusion and essential bacterial cell wall signaling pathways.