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• W2275384704 abstract "New tools and molecules are spurring a renewed interest in natural products. In this issue of Cell Chemical Biology, Zhao and van der Donk, 2016Zhao X. van der Donk W.A. Cell Chem. Biol. 2016; 23 (this issue): 246-256Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar report a single lantibiotic cluster encoding different α- and β-peptides, each with its dedicated processing enzyme. A number of clever experiments led to in vitro production of these molecules. New tools and molecules are spurring a renewed interest in natural products. In this issue of Cell Chemical Biology, Zhao and van der Donk, 2016Zhao X. van der Donk W.A. Cell Chem. Biol. 2016; 23 (this issue): 246-256Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar report a single lantibiotic cluster encoding different α- and β-peptides, each with its dedicated processing enzyme. A number of clever experiments led to in vitro production of these molecules. After a few decades of neglect, natural products are coming back into the spotlight as important sources of drugs leads (e.g., Lewis, 2013Lewis K. Nat. Rev. Drug Discov. 2013; 12: 371-387Crossref PubMed Scopus (952) Google Scholar). This is the result of the failure of alternative technologies to supplant natural products, as well as the development of new tools to access new natural product space. In this respect, genome mining is becoming a powerful tool to identify promising biosynthetic gene clusters (BGCs) worthy of further investigations from the increasingly large number of microbial genomes (e.g., Zotchev et al., 2012Zotchev S.B. Sekurova O.N. Katz L. Curr. Opin. Biotechnol. 2012; 23: 941-947Crossref PubMed Scopus (45) Google Scholar). User-friendly bioinformatic tools can rapidly perform an initial screening of a bacterial genome (Weber et al., 2015Weber T. Blin K. Duddela S. Krug D. Kim H.U. Bruccoleri R. Lee S.Y. Fischbach M.A. Müller R. Wohlleben W. et al.Nucleic Acids Res. 2015; 43: W237-W243Crossref PubMed Scopus (1414) Google Scholar). Among microbial products, RiPPs (ribosomally synthesized post-translationally modified peptides) represent an attractive class to investigate for several reasons: new types of RiPPs are continuously unveiled, with the corresponding post-translational enzymatic machinery (Arnison et al., 2013Arnison P.G. Bibb M.J. Bierbaum G. Bowers A.A. Bugni T.S. Bulaj G. Camarero J.A. Campopiano D.J. Challis G.L. Clardy J. et al.Nat. Prod. Rep. 2013; 30: 108-160Crossref PubMed Scopus (1316) Google Scholar); the corresponding BGCs are found in an increasing number of bacterial taxa; and the sequence of the precursor peptide allows accurate structural prediction, which can also be used to help in elucidating structures of identified compounds (e.g., Iorio et al., 2014Iorio M. Sasso O. Maffioli S.I. Bertorelli R. Monciardini P. Sosio M. Bonezzi F. Summa M. Brunati C. Bordoni R. et al.ACS Chem. Biol. 2014; 9: 398-404Crossref PubMed Scopus (66) Google Scholar). One of the best studied families of RiPPs is the lanthipeptide family, which is characterized by the presence of lanthionine bridges and variations thereof. Despite the impressive progress made in the past decade or so in understanding how lanthipeptides are biosynthesized, this class of compounds continues to yield suprises in terms of new structural features (e.g., Jungmann et al., 2016Jungmann N.A. van Herwerden E.F. Hügelland M. Süssmuth R.D. ACS Chem. Biol. 2016; 11: 69-76Crossref PubMed Scopus (21) Google Scholar) and unsuspected enzymatic mechanisms (Ortega and van der Donk, 2016Ortega M.A. van der Donk W.A. Cell Chem. Biol. 2016; 23: 31-44Abstract Full Text Full Text PDF PubMed Scopus (186) Google Scholar), as well as potential applications against antibiotic-resistant bacterial pathogens (e.g., Maffioli et al., 2015Maffioli S.I. Cruz J.C. Monciardini P. Sosio M. Donadio S. J. Ind. Microbiol. Biotechnol. 2015; (Published online October 29, 2015)http://link.springer.com/article/10.1007%2Fs10295-015-1703-9PubMed Google Scholar). In this context, the paper by Zhao and van der Donk, 2016Zhao X. van der Donk W.A. Cell Chem. Biol. 2016; 23 (this issue): 246-256Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar represents a nice example of the surprises unveiled by genome mining, as well as the sophisticated tools that can be used to turn in silico predictions into actual chemical substances. The authors report an intriguing BGC with considerable genetic redundancy for a class II lanthipeptide from the ruminant bacterium Ruminococcus flavefaciens: the cluster encodes four copies of almost identical FlvA1 peptides and eight copies of rather dissimilar FlvA2 peptides, each set resembling the α- and β-peptide of two-component lantibiotics. The authors demonstrate that each set has its dedicated FlvM enzyme and exploit proteolytic enzymes (another advantage of working with RiPPs) to come as close as possible to what the lanthipeptides may look like in the native host. Finally, the authors show that some peptides alone have antibacterial activity against Micrococcus luteus, whereas some combinations are synergistic. The paper is particularly interesting for the tools employed for achieving production of the lanthipeptides after heterologous expression and enzymatic synthesis. Although the work was inspired by the unusual arrangement of the R. flavofaciens BGC, the significance of such genetic redundancy is only partially addressed; however, preliminary results hint at the possibility of a different antibacterial spectrum of the individual lanthipeptides or combinations thereof. As is often the case in such studies, despite different attempts, Zhao and van der Donk were unable to identify the conditions that allowed lanthipeptide production by R. flavifaciens. Personally, I find that the paper by Zhao and van der Donk delivers at the same time exciting and sobering lessons. On the exciting side, the combination of genome mining, structural prediction, and tools to effectively produce lanthipeptides has reached a point where we can expect to produce most of the molecules identified this way (see Figure 1). Paradoxically, however, it appears that the more we discover about microbial products, the less we know about their roles and activities. In the specific case of R. flavifaciens, three related questions remain unanswered: under which conditions are these lanthipeptides produced by the natural host; which roles do these compounds play for the producer; and, especially, is each FlvA2 lanthipeptide dedicated to a different function? As is often the case for genome-driven approaches, the original hosts might not be immediately accessible to genetic manipulation, limiting the number of tools that can be used to address those questions. Natural products have provided important tools to probe fundamental biological processes and a large number of drugs for human, veterinary, and agricultural applications. Genome mining has introduced a paradigm shift versus bioactivity-based screening in the discovery of new natural products, especially from microbial sources (see Figure 1). This approach allows the “seeing” of molecules that escaped the biases of previous approaches, which relied on production of the desired compound by the original strain under laboratory conditions at concentrations sufficient to allow detection by the selected method (Monciardini et al., 2014Monciardini P. Iorio M. Maffioli S. Sosio M. Donadio S. Microb. Biotechnol. 2014; 7: 209-220Crossref PubMed Scopus (116) Google Scholar). In the genome-mining approach, compounds of interest can be produced in the native host, after heterologous expression or through enzymatic synthesis. So, few options are available and, with sufficient effort, partial or complete production of the desired compound can be achieved, as Zhao and van der Donk nicely demonstrate. At the same time, however, we are still ill-equipped to advance through the next step, going from structure to bioactivity and, possibly, function (see Figure 1). Progress in this area cannot be expected from a single laboratory or institution, but might require a concerted effort and centralized resources for scientists to evaluate the activity of newly discovered compounds. Structural Characterization and Bioactivity Analysis of the Two-Component Lantibiotic Flv System from a Ruminant BacteriumZhao et al.Cell Chemical BiologyJanuary 28, 2016In BriefAn unusual gene cluster from Ruminococcus flavefaciens contains 12 substrate and two lanthipeptide synthetase genes. The post-translationally modified peptides were produced in E. coli and comprise four structurally conserved lipid II binding peptides and eight structurally diverse β-peptides, some of which displayed synergistic antimicrobial activity. Full-Text PDF Open Archive" @default.
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• W2275384704 date "2016-02-01" @default.
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• W2275384704 title "Combinatorial Lanthipeptides from a Ruminant Bacterium" @default.
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