Heterologous Production of Microbial Ribosomally Synthesized and Post-translationally Modified Peptides

Abstract

Ribosomally synthesized and post-translationally modified peptides, or RiPPs, which have mainly isolated from microbes as well as plants and animals, are an ever-expanding group of peptidic natural products with diverse chemical structures and biological activities. They have emerged as a major category of secondary metabolites partly due to a myriad of microbial genome sequencing endeavors and the availability of genome mining software in the past two decades. Heterologous expression of RiPP gene clusters mined from microbial genomes, which are often silent in native producers, in surrogate hosts such as Escherichia coli and Streptomyces strains can be an effective way to elucidate encoded peptides and produce novel derivatives. Emerging strategies have been developed to facilitate the success of the heterologous expression by targeting multiple synthetic biology levels, including individual proteins, pathways, metabolic flux and hosts. This review describes recent advances in heterologous production of RiPPs, mainly from microbes, with a focus on E. coli and Streptomyces strains as the surrogate hosts.

Roseocin, a novel two‐component lantibiotic from an actinomycete

“…The Classes III and IV lanthipeptides majorly display bioactivities other than antimicrobial, like morphogenetic (Ueda et al, ), antiviral, antiallodynic (Férir et al, ), antinociceptive (Iorio et al, ) and antidiabetic activities (Iftime et al, ). The Class II lantibiotics are processed by a single lanthionine synthetase and are also the most studied lantibiotics by heterologous expression (Zhang, Chen, Bruner, & Ding, ).…”

Engineering of Streptomyces lividans for heterologous expression of secondary metabolite gene clusters

“…The latter metabolite was not produced by S. albus Del14 when the respective construct was introduced. It is also well known that S. lividans is a long-term preferred host for ribosomally synthesized and post-translationally modified peptide (RiPP) gene cluster expression [59,60]. At the same time, the polyketide griseorhodin was not produced by S. lividans TK24 at all, and S. albus Del14 was superior to all other strains tested in this work.…”

Combating Antimicrobial Resistance With New-To-Nature Lanthipeptides Created by Genetic Code Expansion

“…Therefore, their recombinant expression has to be coupled with the co-expression of active PTM biosynthetic gene clusters either in vitro or in vivo. These strategies are not in the focus of our study and interested readers are directed to numerous studies and reviews dedicated to this topic (Zhang et al, 2018;Myronovskyi and Luzhetskyy, 2019). We are mainly concerned with the in vivo design strategies that focus to expand the functional scope of AMPs from ribosomal templates beyond the classical protein engineering approaches.…”

“…However, Escherichia coli is still the most common and attractive option. A list of successful examples of recombinant expression of different RiPPs families in heterologous hosts such as E. coli and Streptomyces strains were recently compiled by Zhang and colleagues ( Zhang et al, 2018 ). Heterologous production of lantibiotics is generally conducted as inactive form of the antimicrobial peptide (pre-lantibiotic) to prevent any detrimental effects on host cell growth and viability.…”