This review provides a comprehensive update of the advances in discovery, biosynthesis, and engineering of ribosomally-synthesized and post-translationally modified peptides (RiPPs).

Due to the challenges of antibiotic resistance to global health, bacteriocins as antimicrobial compounds have received more and more attention. Bacteriocins are biosynthesized by various microbes and are predominantly used as food preservatives to control foodborne pathogens. Now, increasing researches have focused on bacteriocins as potential clinical antimicrobials or immune‐modulating agents to fight against the global threat to human health. Given the broad‐ or narrow‐spectrum antimicrobial activity, bacteriocins have been reported to inhibit a wide range of clinically pathogenic and multidrug‐resistant bacteria, thus preventing the infections caused by these bacteria in the human body. Otherwise, some bacteriocins also show anticancer, anti‐inflammatory, and immune‐modulatory activities. Because of the safety and being not easy to cause drug resistance, some bacteriocins appear to have better efficacy and application prospects than existing therapeutic agents do. In this review, we highlight the potential therapeutic activities of bacteriocins and suggest opportunities for their application.

Nisin is a 34-residue antibacterial peptide produced by Lactococcus lactis that is active against a wide range of gram-positive bacteria. In non-nisin-producing L. lactis , nisin resistance could be conferred by a specific nisin resistance gene ( nsr ), which encodes a 35-kDa nisin resistance protein (NSR). However, the mechanism underlying NSR-mediated nisin resistance is poorly understood. Here we demonstrated that the protein without the predicted N-terminal signal peptide sequence, i.e., NSRSD, could proteolytically inactivate nisin in vitro by removing six amino acids from the carboxyl “tail” of nisin. The truncated nisin (nisin ^1-28 ) displayed a markedly reduced affinity for the cell membrane and showed significantly diminished pore-forming potency in the membrane. A 100-fold reduction of bactericidal activity was detected for nisin ^1-28 in comparison to that for the intact nisin. In vivo analysis indicated that NSR localized on the cell membrane and endowed host strains with nisin resistance by degrading nisin as NSRSD did in vitro, whereas NSRSD failed to confer resistance upon the host strain. In conclusion, we showed that NSR is a nisin-degrading protease. This NSR-mediated proteolytic cleavage represents a novel mechanism for nisin resistance in non-nisin-producing L. lactis .