Discovery of the Class I Antimicrobial Lasso Peptide Arcumycin

Lasso peptides are a structurally diverse superfamily of

conformationally-constrained peptide natural products, of which a

subset exhibits broad antimicrobial activity. Although advances in

bioinformatics have increased our knowledge of strains harboring

the biosynthetic machinery for lasso peptide production, relating

peptide sequence to bioactivity remains a continuous challenge.

Towards this end, a structure-driven genome mining investigation

of Actinobacteria-produced antimicrobial lasso peptides was

performed to correlate predicted primary structure with antibiotic

activity. Bioinformatic evaluation revealed eight putative novel

class I lasso peptide sequences. This subset is predicted to

possess antibiotic activity as characterized members of this class

have both broad spectrum and potent activity against Gram positive

strains. Fermentation of one of these hits, Streptomyces

NRRL F-5639, resulted in the production of a novel class I lasso

peptide, arcumycin, named for the Latin word for bow or arch,

arcum. Arcumycin exhibited antibiotic activity against Gram positive

bacteria including Bacillus subtilis (4 μg/mL),

Staphylococcus aureus (8 μg/mL), and Micrococcus luteus (8

μg/mL). Arcumycin treatment of B. subtilis liaI-β-gal promoter

fusion reporter strain resulted in upregulation of the system liaRS

by the promoter liaI, indicating arcumycin interferes with lipid II

biosynthesis. Cumulatively, the results illustrate the relationship

between phylogenetically related lasso peptides and their

bioactivity as validated through the isolation, structural

determination, and evaluation of bioactivity of the novel class I

antimicrobial lasso peptide arcumycin.