The lanthipeptide mersacidin is a ribosomally synthesized and post-translationally modified peptide (RiPP) produced by Bacillus amyloliquefaciens. It has antimicrobial activity against a range of Gram-positive bacteria, including methicillinresistant Staphylococcus aureus, giving it potential therapeutic relevance. The structure and bioactivity of mersacidin are derived from a unique combination of lanthionine ring structures, which makes mersacidin also interesting from a lantibiotic-engineering point of view. Until now, mersacidin and its derivatives have exclusively been produced in Bacillus strains and purified from the supernatant in their bioactive form. However, to fully exploit its potential in lanthipeptide-engineering, mersacidin would have to be expressed in a standardized expression system and obtained in its inactive prepeptide form. In such a system, the mersacidin biosynthetic enzymes could be employed to create novel peptides, enhanced by the recent advancements in RiPP engineering, while the leader peptide prevents activity against the expression host. This system would however need a means of postpurification in vitro leader processing to activate the obtained precursor peptides. While mersacidin's native leader processing mechanism has not been confirmed, the bifunctional transporter MrsT and extracellular Bacillus proteases have been suggested to be responsible. Here, a modular system is presented for the heterologous expression of mersacidin in Escherichia coli, which was successfully used to produce and purify inactive premersacidin. The purified product was used to determine the cleavage site of MrsT. Additionally, it was concluded from antimicrobial activity tests that in a second processing step mersacidin is activated by specific extracellular proteases from Bacillus amyloliquefaciens.

The emergence and re-emergence of viral epidemics and the risks of antiviral drug resistance are a serious threat to global public health. New options to supplement or replace currently used drugs for antiviral therapy are urgently needed. The research in the field of ribosomally synthesized and post-translationally modified peptides (RiPPs) has been booming in the last few decades, in particular in view of their strong antimicrobial activities and high stability. The RiPPs with antiviral activity, especially those against enveloped viruses, are now also gaining more interest. RiPPs have a number of advantages over small molecule drugs in terms of specificity and affinity for targets, and over protein-based drugs in terms of cellular penetrability, stability and size. Moreover, the great engineering potential of RiPPs provides an efficient way to optimize them as potent antiviral drugs candidates. These intrinsic advantages underscore the good therapeutic prospects of RiPPs in viral treatment. With the aim to highlight the underrated antiviral potential of RiPPs and explore their development as antiviral drugs, we review the current literature describing the antiviral activities and mechanisms of action of RiPPs, discussing the ongoing efforts to improve their antiviral potential and demonstrate their suitability as antiviral therapeutics. We propose that antiviral RiPPs may overcome the limits of peptide-based antiviral therapy, providing an innovative option for the treatment of viral disease.