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Review
, 295 (1), 34-54

The Manifold Roles of Microbial Ribosomal Peptide-Based Natural Products in Physiology and Ecology

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Review

The Manifold Roles of Microbial Ribosomal Peptide-Based Natural Products in Physiology and Ecology

Yanyan Li et al. J Biol Chem.

Abstract

The ribosomally synthesized and posttranslationally modified peptides (RiPPs), also called ribosomal peptide natural products (RPNPs), form a growing superfamily of natural products that are produced by many different organisms and particularly by bacteria. They are derived from precursor polypeptides whose modification by various dedicated enzymes helps to establish a vast array of chemical motifs. RiPPs have attracted much interest as a source of potential therapeutic agents, and in particular as alternatives to conventional antibiotics to address the bacterial resistance crisis. However, their ecological roles in nature are poorly understood and explored. The present review describes major RiPP actors in competition within microbial communities, the main ecological and physiological functions currently evidenced for RiPPs, and the microbial ecosystems that are the sites for these functions. We envision that the study of RiPPs may lead to discoveries of new biological functions and highlight that a better knowledge of how bacterial RiPPs mediate inter-/intraspecies and interkingdom interactions will hold promise for devising alternative strategies in antibiotic development.

Keywords: antimicrobial peptide (AMP); bacteria; bacterial communication; bacteriocin; biofilm; ecological strategies; microbial competition; natural product; ribosomal peptide natural product (RPNP); ribosomally synthesized and post-translationally modified peptide (RiPP).

Conflict of interest statement

The authors declare that they have no conflicts of interest with the contents of this article.

Figures

Figure 1.
Figure 1.
General biosynthetic pathway leading to RiPP production, from the gene cluster to the mature active compound. The ribosomally synthesized precursor can be only cleaved by a protease (green) and exported by an ABC transporter (brown) as an unmodified peptide. For RiPP biosynthesis, the core peptide is fused to a leader peptide (gray) that contributes to the action of the posttranslational modification enzymes (blue). Cleavage of the leader and export of the RiPP are both generally ensured by a peptidase-containing ATP-binding transporter (PCAT) that accomplishes the two functions.
Figure 2.
Figure 2.
Representative structures of different classes of RiPPs cited in this review. Unmodified amino acids are circled. In the microcin J25 structure, the residues forming the macrolactam linkage and entrapping the tail within the ring by steric hindrance are highlighted in green and red, respectively.
Figure 3.
Figure 3.
Schematic of the main strategies of Gram-negative (A) and -positive (B) bacteria for colonization resistance and competition involving RPNPs. 1, interference competition using RPNPs as contact-dependent killer molecules (several examples from both Gram-negative and -positive bacteria, among which are the lasso peptide microcin J25 and the two-peptide sactibiotic thuricin CD, respectively); 2, exploitative competition exemplified by the battle for iron involving competition between siderophores and siderophore-modified peptides for the same high affinity receptors (MccE492m from K. pneumoniae RYC 492 and MccH47 from E. coli Nissle 1917); 3, reservoir of killing RPNPs using functional amyloids for delivering killers (MccE492 from K. pneumoniae RYC 492); 4, synergy between RPNPs and host AMPs (Sh-lantibiotic-α and Sh-lantibiotic-β from S. hominis A9, each synergizing with the host cathelicidin LL-37); 5, quorum-sensing interference (an autoinducing RPNP from S. hominis A9 acts as a disruptor of quorum sensing that inhibits the secretion of the virulence factor PSMα in S. aureus; 6, cooperation between host and RPNP producing bacterium in the gut for the final processing step leading to mature RPNP acting by interference competition (ruminococcin C from R. gnavus E1); 7, manipulation of commensals by the pathogen to occupy the niche and increase virulence (the pathogenic strain L. monocytogenes F2365 produces listeriolysin S, a TOMM virulence factor, which targets commensal bacteria occupying the same niche and devoid of self-immunity to the toxin, to increase nutrient level and favor invasion).
Figure 4.
Figure 4.
Schematic summary of known microbial RiPP functions in the context of interkingdom, interspecies, and intraspecies interactions.

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