Phylogeny-guided genome mining of roseocin family lantibiotics to generate improved variants of roseocin
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Published:2023-03-20
Issue:1
Volume:13
Page:
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ISSN:2191-0855
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Container-title:AMB Express
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language:en
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Short-container-title:AMB Expr
Author:
Chaudhary Sandeep, Kishen Shweta, Singh Mangal, Jassal Sunanda, Pathania Reeva, Bisht Kalpana, Sareen DiptiORCID
Abstract
AbstractRoseocin, the two-peptide lantibiotic from Streptomyces roseosporus, carries extensive intramolecular (methyl)lanthionine bridging in the peptides and exhibits synergistic antibacterial activity against clinically relevant Gram-positive pathogens. Both peptides have a conserved leader but a diverse core region. The biosynthesis of roseocin involves post-translational modification of the two precursor peptides by a single promiscuous lanthipeptide synthetase, RosM, to install an indispensable disulfide bond in the Rosα core along with four and six thioether rings in Rosα and Rosβ cores, respectively. RosM homologs in the phylum actinobacteria were identified here to reveal twelve other members of the roseocin family which diverged into three types of biosynthetic gene clusters (BGCs). Further, the evolutionary rate among the BGC variants and analysis of variability within the core peptide versus leader peptide revealed a phylum-dependent lanthipeptide evolution. Analysis of horizontal gene transfer revealed its role in the generation of core peptide diversity. The naturally occurring diverse congeners of roseocin peptides identified from the mined novel BGCs were carefully aligned to identify the conserved sites and the substitutions in the core peptide region. These selected sites in the Rosα peptide were mutated for permitted substitutions, expressed heterologously in E. coli, and post-translationally modified by RosM in vivo. Despite a limited number of generated variants, two variants, RosαL8F and RosαL8W exhibited significantly improved inhibitory activity in a species-dependent manner compared to the wild-type roseocin. Our study proves that a natural repository of evolved variants of roseocin is present in nature and the key variations can be used to generate improved variants.
Funder
Council for Scientific and Industrial Research, New Delhi DST-SERB University Grants Commission-Special Assistance Programme
Publisher
Springer Science and Business Media LLC
Subject
Applied Microbiology and Biotechnology,Biophysics
Reference71 articles.
1. Abts A, Montalban-Lopez M, Kuipers OP, Smits SH, Schmitt L (2013) NisC binds the FxLx motif of the nisin leader peptide. Biochemistry 52:5387–5395. https://doi.org/10.1021/bi4008116 2. Adamek M, Alanjary M, Ziemert N (2019) Applied evolution: phylogeny-based approaches in natural products research. Nat Prod Rep 36:1295–1312. https://doi.org/10.1039/c9np00027e 3. Arias-Orozco P, Inklaar M, Lanooij J, Cebrián R, Kuipers OP (2021) Functional expression and characterization of the highly promiscuous lanthipeptide synthetase SyncM, enabling the production of lanthipeptides with a broad range of ring topologies. ACS Synth Biol 10:2579–2591. https://doi.org/10.1021/acssynbio.1c00224 4. Arnison PG, Bibb MJ, Bierbaum G, Bowers AA, Bugni TS, Bulaj G, Camarero JA, Campopiano DJ, Challis GL, Clardy J, Cotter PD, Craik DJ, Dawson M, Dittmann E, Donadio S, Dorrestein PC, Entian KD, Fischbach MA, Garavelli JS, Göransson U, Gruber CW, Haft DH, Hemscheidt TK, Hertweck C, Hill C, Horswill AR, Jaspars M, Kelly WL, Klinman JP, Kuipers OP, Link AJ, Liu W, Marahiel MA, Mitchell DA, Moll GN, Moore BS, Müller R, Nair SK, Nes IF, Norris GE, Olivera BM, Onaka H, Patchett ML, Piel J, Reaney MJT, Rebuffat S, Ross RP, Sahl HG, Schmidt EW, Selsted ME, Severinov K, Shen B, Sivonen K, Smith L, Stein T, Süssmuth RD, Tagg JR, Tang GL, Truman AW, Vederas JC, Walsh CT, Walton JD, Wenzel SC, Willey JM, Van Der Donk WA (2013) Ribosomally synthesized and post-translationally modified peptide natural products: overview and recommendations for a universal nomenclature. Nat Prod Rep 30:108–160. https://doi.org/10.1039/c2np20085f 5. Bakhtiary A, Cochrane SA, Mercier P, McKay RT, Miskolzie M, Sit CS, Vederas JC (2017) Insights into the mechanism of action of the two-peptide lantibiotic lacticin 3147. J Am Chem Soc 139:17803–17810. https://doi.org/10.1021/jacs.7b04728
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