Pangenome Analysis of Enterobacteria Reveals Richness of Secondary Metabolite Gene Clusters and Their Associated Gene Sets

Overview

Journal Synth Syst Biotechnol

Specialty Biotechnology

Date 2022 Jun 1

PMID 35647330

Authors

Omkar S Mohite

Colton J Lloyd

Jonathan M Monk

Tilmann Weber

Bernhard O Palsson

Affiliations

Soon will be listed here.

Abstract

In silico genome mining provides easy access to secondary metabolite biosynthetic gene clusters (BGCs) encoding the biosynthesis of many bioactive compounds, which are the basis for many important drugs used in human medicine. However, the association between BGCs and other functions encoded in the genomes of producers have remained elusive. Here, we present a systems biology workflow that integrates genome mining with a detailed pangenome analysis for detecting genes associated with a particular BGC. We analyzed 3,889 enterobacterial genomes and found 13,266 BGCs, represented by 252 distinct BGC families and 347 additional singletons. A pangenome analysis revealed 88 genes putatively associated with a specific BGC coding for the colon cancer-related colibactin that code for diverse metabolic and regulatory functions The presented workflow opens up the possibility to discover novel secondary metabolites, better understand their physiological roles, and provides a guide to identify and analyze BGC associated gene sets.

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References

Lam M, Wyres K, Judd L, Wick R, Jenney A, Brisse S . Tracking key virulence loci encoding aerobactin and salmochelin siderophore synthesis in Klebsiella pneumoniae. Genome Med. 2018; 10(1):77. PMC: 6205773. DOI: 10.1186/s13073-018-0587-5. View

Antonopoulos D, Assaf R, Aziz R, Brettin T, Bun C, Conrad N . PATRIC as a unique resource for studying antimicrobial resistance. Brief Bioinform. 2017; 20(4):1094-1102. PMC: 6781570. DOI: 10.1093/bib/bbx083. View

Donia M, Cimermancic P, Schulze C, Wieland Brown L, Martin J, Mitreva M . A systematic analysis of biosynthetic gene clusters in the human microbiome reveals a common family of antibiotics. Cell. 2014; 158(6):1402-1414. PMC: 4164201. DOI: 10.1016/j.cell.2014.08.032. View

Tobias N, Wolff H, Djahanschiri B, Grundmann F, Kronenwerth M, Shi Y . Natural product diversity associated with the nematode symbionts Photorhabdus and Xenorhabdus. Nat Microbiol. 2017; 2(12):1676-1685. DOI: 10.1038/s41564-017-0039-9. View

Wu H, Yang Z, Yang T, Wang D, Luo H, Gao F . An Effective Preprocessing Method for High-Quality Pan-Genome Analysis of Bacillus subtilis and Escherichia coli. Methods Mol Biol. 2021; 2377:371-390. DOI: 10.1007/978-1-0716-1720-5_21. View

Tobias N, Shi Y, Bode H . Refining the Natural Product Repertoire in Entomopathogenic Bacteria. Trends Microbiol. 2018; 26(10):833-840. DOI: 10.1016/j.tim.2018.04.007. View

Cimermancic P, Medema M, Claesen J, Kurita K, Wieland Brown L, Mavrommatis K . Insights into secondary metabolism from a global analysis of prokaryotic biosynthetic gene clusters. Cell. 2014; 158(2):412-421. PMC: 4123684. DOI: 10.1016/j.cell.2014.06.034. View

Shneider M, Buth S, Ho B, Basler M, Mekalanos J, Leiman P . PAAR-repeat proteins sharpen and diversify the type VI secretion system spike. Nature. 2013; 500(7462):350-353. PMC: 3792578. DOI: 10.1038/nature12453. View

Wami H, Wallenstein A, Sauer D, Stoll M, von Bunau R, Oswald E . Insights into evolution and coexistence of the colibactin- and yersiniabactin secondary metabolite determinants in enterobacterial populations. Microb Genom. 2021; 7(6). PMC: 8461471. DOI: 10.1099/mgen.0.000577. View

10.

Nougayrede J, Homburg S, Taieb F, Boury M, Brzuszkiewicz E, Gottschalk G . Escherichia coli induces DNA double-strand breaks in eukaryotic cells. Science. 2006; 313(5788):848-51. DOI: 10.1126/science.1127059. View

11.

Blin K, Shaw S, Steinke K, Villebro R, Ziemert N, Lee S . antiSMASH 5.0: updates to the secondary metabolite genome mining pipeline. Nucleic Acids Res. 2019; 47(W1):W81-W87. PMC: 6602434. DOI: 10.1093/nar/gkz310. View

12.

Gerc A, Song L, Challis G, Stanley-Wall N, Coulthurst S . The insect pathogen Serratia marcescens Db10 uses a hybrid non-ribosomal peptide synthetase-polyketide synthase to produce the antibiotic althiomycin. PLoS One. 2012; 7(9):e44673. PMC: 3445576. DOI: 10.1371/journal.pone.0044673. View

13.

Dougherty M, Jobin C . Shining a Light on Colibactin Biology. Toxins (Basel). 2021; 13(5). PMC: 8151066. DOI: 10.3390/toxins13050346. View

14.

Shi Y, Hirschmann M, Shi Y, Ahmed S, Abebew D, Tobias N . Global analysis of biosynthetic gene clusters reveals conserved and unique natural products in entomopathogenic nematode-symbiotic bacteria. Nat Chem. 2022; 14(6):701-712. PMC: 9177418. DOI: 10.1038/s41557-022-00923-2. View

15.

Wilson M, Jiang Y, Villalta P, Stornetta A, Boudreau P, Carra A . The human gut bacterial genotoxin colibactin alkylates DNA. Science. 2019; 363(6428). PMC: 6407708. DOI: 10.1126/science.aar7785. View

16.

Genilloud O . Mining Actinomycetes for Novel Antibiotics in the Omics Era: Are We Ready to Exploit This New Paradigm?. Antibiotics (Basel). 2018; 7(4). PMC: 6316141. DOI: 10.3390/antibiotics7040085. View

17.

Maglangit F, Yu Y, Deng H . Bacterial pathogens: threat or treat (a review on bioactive natural products from bacterial pathogens). Nat Prod Rep. 2020; 38(4):782-821. DOI: 10.1039/d0np00061b. View

18.

Palazzotto E, Weber T . Omics and multi-omics approaches to study the biosynthesis of secondary metabolites in microorganisms. Curr Opin Microbiol. 2018; 45:109-116. DOI: 10.1016/j.mib.2018.03.004. View

19.

Murase K, Martin P, Porcheron G, Houle S, Helloin E, Penary M . HlyF Produced by Extraintestinal Pathogenic Escherichia coli Is a Virulence Factor That Regulates Outer Membrane Vesicle Biogenesis. J Infect Dis. 2015; 213(5):856-65. DOI: 10.1093/infdis/jiv506. View

20.

Ren Y, Palusiak A, Wang W, Wang Y, Li X, Wei H . A High-resolution Typing Assay for Uropathogenic Escherichia coli Based on Fimbrial Diversity. Front Microbiol. 2016; 7:623. PMC: 4850163. DOI: 10.3389/fmicb.2016.00623. View