Abstract
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.