Translation-Targeting RiPPs and Where to Find Them

Abstract

Prokaryotic translation is among the major targets of diverse natural products with antibacterial activity including several classes of clinically relevant antibiotics. In this review, we summarize the information about the structure, biosynthesis, and modes of action of translation inhibiting ribosomally synthesized and post-translationally modified peptides (RiPPs). Azol(in)e-containing RiPPs are known to target translation, and several new compounds inhibiting the ribosome have been characterized recently. We performed a systematic search for biosynthetic gene clusters (BGCs) of azol(in)econtaining RiPPs. This search uncovered several groups of clusters that likely direct the synthesis of novel compounds, some of which may be targeting the ribosome.

A scalable platform to discover antimicrobials of ribosomal origin

“…Linear azol(in)e-containing peptides (LAPs) constitute another major class of RiPPs, which are characterized by the presence of azole or azoline heterocycles formed through cyclodehydrations and dehydrogenations of Cys/Thr/Ser within a linear peptide 52 . To date, 17 LAPs are known, most of which show cytolytic activity (streptolysin S, clostridiolysin S, listeriolysin S) or narrow-spectrum antibacterial activities by inhibiting DNA-gyrase (microcin B17) or the ribosome (klebsazolicin, phazolicin) 3 . Using the FAST-RiPPs pipeline, nine out of ten BGCs from four different phyla were successfully refactored.…”

“…Ribosomally synthesized and post-translationally modified peptides (RiPPs) constitute a major group of natural products exhibiting a range of biological activities, including antibacterial and antiviral activities 1 , 2 . As antimicrobial resistance has become a growing crisis, RiPPs have garnered significant attention, with many possessing modes of action distinct from clinically used antimicrobials 3 , 4 . Of particular interest are RiPPs that are active against the ESKAPE pathogens 5 – 7 , a group of six nosocomial pathogens that are capable of escaping biocidal activity of available antibiotics: Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp 8 .…”

Biological Dark Matter Exploration using Data Mining for the Discovery of Antimicrobial Natural Products

“…Recent advances in the discovery of new antimicrobials by genome mining include the exploration of new species from the Proteobacteria, Firmicutes and Actinobacteria taxa 33 , 34 , enhancing the ability to predict and prioritize novel BGCs.…”

Bacteriocins to Thwart Bacterial Resistance in Gram Negative Bacteria

“…The development of DNA sequencing methods and the availability of an increasing number of genomes revealed that clusters of genes orthologous to microcin biosynthesis and self-immunity genes are widespread in bacteria. Indeed, analogs of historically described microcins produced by Enterobacteriaceae , essentially in the RiPP family, have been predicted and most often deeply characterized in other Gram-negative bacteria including human pathogens, Helicobacter ( Bantysh et al, 2014 ), Burkholderia ( Knappe et al, 2008 ), Pseudomonas ( Metelev et al, 2013 ), Klebsiella ( Metelev et al, 2017a , b ; Travin et al, 2020 ), Acinetobacter ( Metelev et al, 2017a ), Citrobacter ( Cheung-Lee et al, 2019 ), or in the symbiotic nitrogen-fixing bacterium Rhizobium ( Travin et al, 2019 ) ( Supplementary Figure S1A ). They were even predicted in Gram-positive bacteria and cyanobacteria ( Bantysh et al, 2014 ).…”