Lasso peptides are members of the
natural product superfamily of
ribosomally synthesized and post-translationally modified peptides
(RiPPs). Here, we describe the first lasso peptide originating from
a biosynthetic gene cluster belonging to a unique lasso peptide subclade
defined by the presence of a bifunctional protein harboring both a
leader peptidase (B2) and an ABC transporter (D) domain. Bioinformatic
analysis revealed that these clusters also encode homologues of the
NisR/NisK regulatory system and the NisF/NisE/NisG immunity factors,
which are usually associated with the clusters of antimicrobial class
I lanthipeptides, such as nisin, another distinct RiPP subfamily.
The cluster enabling the heterologous production of the lasso peptide
cochonodin I in E. coli originated from Streptococcus
suis LSS65, and the threaded structure of cochonodin I was
evidenced through extensive MS/MS analysis and stability assays. It
was shown that the ABC transporter domain from SsuB2/D is not essential
for lasso peptide maturation. By extensive genome mining dedicated
exclusively to other lasso peptide biosynthetic gene clusters featuring
bifunctional B2/D proteins, it was furthermore revealed that many
bacteria associated with human or animal microbiota hold the biosynthetic
potential to produce cochonodin-like lasso peptides, implying that
these natural products might play roles in human and animal health.