ARTS 2.0: feature updates and expansion of the Antibiotic Resistant Target Seeker for comparative genome mining

Abstract Multi-drug resistant pathogens have become a major threat to human health and new antibiotics are urgently needed. Most antibiotics are derived from secondary metabolites produced by bacteria. In order to avoid suicide, these bacteria usually encode resistance genes, in some cases within the biosynthetic gene cluster (BGC) of the respective antibiotic compound. Modern genome mining tools enable researchers to computationally detect and predict BGCs that encode the biosynthesis of secondary metabolites. The major challenge now is the prioritization of the most promising BGCs encoding antibiotics with novel modes of action. A recently developed target-directed genome mining approach allows researchers to predict the mode of action of the encoded compound of an uncharacterized BGC based on the presence of resistant target genes. In 2017, we introduced the ‘Antibiotic Resistant Target Seeker’ (ARTS). ARTS allows for specific and efficient genome mining for antibiotics with interesting and novel targets by rapidly linking housekeeping and known resistance genes to BGC proximity, duplication and horizontal gene transfer (HGT) events. Here, we present ARTS 2.0 available at http://arts.ziemertlab.com. ARTS 2.0 now includes options for automated target directed genome mining in all bacterial taxa as well as metagenomic data. Furthermore, it enables comparison of similar BGCs from different genomes and their putative resistance genes.

[1]  Emma J. Chory,et al.  A Deep Learning Approach to Antibiotic Discovery , 2020, Cell.

[2]  I-Min A. Chen,et al.  IMG-ABC v.5.0: an update to the IMG/Atlas of Biosynthetic Gene Clusters Knowledgebase , 2019, Nucleic Acids Res..

[3]  Roger G. Linington,et al.  MIBiG 2.0: a repository for biosynthetic gene clusters of known function , 2019, Nucleic Acids Res..

[4]  Justin J. J. van der Hooft,et al.  The Natural Products Atlas: An Open Access Knowledge Base for Microbial Natural Products Discovery , 2019, ACS central science.

[5]  Marnix H. Medema,et al.  A computational framework to explore large-scale biosynthetic diversity , 2019, Nature Chemical Biology.

[6]  Danny A. Bitton,et al.  A deep learning genome-mining strategy for biosynthetic gene cluster prediction , 2019, Nucleic acids research.

[7]  S. Lee,et al.  antiSMASH 5.0: updates to the secondary metabolite genome mining pipeline , 2019, Nucleic Acids Res..

[8]  F. Barona-Gómez,et al.  EvoMining reveals the origin and fate of natural product biosynthetic enzymes , 2018, bioRxiv.

[9]  Kai Blin,et al.  The antiSMASH database version 2: a comprehensive resource on secondary metabolite biosynthetic gene clusters , 2018, Nucleic Acids Res..

[10]  Yuemao Shen,et al.  Discovery of novel bioactive natural products driven by genome mining. , 2018, Drug discoveries & therapeutics.

[11]  Yoji Nakamura.  Prediction of Horizontally and Widely Transferred Genes in Prokaryotes , 2018, Evolutionary bioinformatics online.

[12]  R. Müller,et al.  Future Directions of Marine Myxobacterial Natural Product Discovery Inferred from Metagenomics , 2018, Marine drugs.

[13]  K. Hughes,et al.  Thailandamide, a Fatty Acid Synthesis Antibiotic That Is Coexpressed with a Resistant Target Gene , 2018, Antimicrobial Agents and Chemotherapy.

[14]  S. Jacobsen,et al.  Resistance-Gene Directed Discovery of a Natural Product Herbicide with a New Mode of Action , 2018, Nature.

[15]  B. Philmus,et al.  Self-Resistance of Natural Product Producers: Past, Present, and Future Focusing on Self-Resistant Protein Variants. , 2018, ACS chemical biology.

[16]  Chao Zhang,et al.  ASTRAL-III: polynomial time species tree reconstruction from partially resolved gene trees , 2018, BMC Bioinformatics.

[17]  Kai Blin,et al.  The Antibiotic Resistant Target Seeker (ARTS), an exploration engine for antibiotic cluster prioritization and novel drug target discovery , 2017, Nucleic Acids Res..

[18]  Michael A. Skinnider,et al.  PRISM 3: expanded prediction of natural product chemical structures from microbial genomes , 2017, Nucleic Acids Res..

[19]  D. M. Vienne.  Lifemap: Exploring the Entire Tree of Life. , 2016 .

[20]  Tilmann Weber,et al.  The evolution of genome mining in microbes - a review. , 2016, Natural product reports.

[21]  Brian C. Thomas,et al.  A new view of the tree of life , 2016, Nature Microbiology.

[22]  Heebal Kim,et al.  HGTree: database of horizontally transferred genes determined by tree reconciliation , 2015, Nucleic Acids Res..

[23]  Wen J. Li,et al.  Reference sequence (RefSeq) database at NCBI: current status, taxonomic expansion, and functional annotation , 2015, Nucleic Acids Res..

[24]  Brian D. Ondov,et al.  Mash: fast genome and metagenome distance estimation using MinHash , 2015, Genome Biology.

[25]  P. Vrignaud,et al.  Production of the Bengamide Class of Marine Natural Products in Myxobacteria: Biosynthesis and Structure-Activity Relationships. , 2015, Angewandte Chemie.

[26]  B. Moore,et al.  Identification of Thiotetronic Acid Antibiotic Biosynthetic Pathways by Target-directed Genome Mining. , 2015, ACS chemical biology.

[27]  M. Trindade,et al.  Targeted metagenomics as a tool to tap into marine natural product diversity for the discovery and production of drug candidates , 2015, Front. Microbiol..

[28]  Z. Deng,et al.  Ornithine Transcarbamylase ArgK Plays a Dual role for the Self-defense of Phaseolotoxin Producing Pseudomonas syringae pv. phaseolicola , 2015, Scientific Reports.

[29]  H. Vlamakis,et al.  Directed natural product biosynthesis gene cluster capture and expression in the model bacterium Bacillus subtilis , 2015, Scientific Reports.

[30]  K. Ryan,et al.  In vitro reconstitution of indolmycin biosynthesis reveals the molecular basis of oxazolinone assembly , 2015, Proceedings of the National Academy of Sciences.

[31]  A. Harvey,et al.  The re-emergence of natural products for drug discovery in the genomics era , 2015, Nature Reviews Drug Discovery.

[32]  R. Müller,et al.  Cystobactamids: myxobacterial topoisomerase inhibitors exhibiting potent antibacterial activity. , 2014, Angewandte Chemie.

[33]  D. Dominey-Howes,et al.  The Antimicrobial Resistance Crisis: Causes, Consequences, and Management , 2014, Front. Public Health.

[34]  Roger G. Linington,et al.  Insights into Secondary Metabolism from a Global Analysis of Prokaryotic Biosynthetic Gene Clusters , 2014, Cell.

[35]  Yan Lin,et al.  DEG 10, an update of the database of essential genes that includes both protein-coding genes and noncoding genomic elements , 2013, Nucleic Acids Res..

[36]  Brian O. Bachmann,et al.  Microbial genome mining for accelerated natural products discovery: is a renaissance in the making? , 2014, Journal of Industrial Microbiology & Biotechnology.

[37]  Nicholas Waglechner,et al.  Identifying producers of antibacterial compounds by screening for antibiotic resistance , 2013, Nature Biotechnology.

[38]  P. Jensen,et al.  Multilocus Sequence Typing Reveals Evidence of Homologous Recombination Linked to Antibiotic Resistance in the Genus Salinispora , 2013, Applied and Environmental Microbiology.

[39]  David J Newman,et al.  Natural products: a continuing source of novel drug leads. , 2013, Biochimica et biophysica acta.

[40]  Erin Beck,et al.  TIGRFAMs and Genome Properties in 2013 , 2012, Nucleic Acids Res..

[41]  David J Newman,et al.  Natural products as sources of new drugs over the 30 years from 1981 to 2010. , 2012, Journal of natural products.

[42]  R. Müller,et al.  Myxobacterium-Produced Antibiotic TA (Myxovirescin) Inhibits Type II Signal Peptidase , 2012, Antimicrobial Agents and Chemotherapy.

[43]  P. Bonin,et al.  Caldilinea tarbellica sp. nov., a filamentous, thermophilic, anaerobic bacterium isolated from a deep hot aquifer in the Aquitaine Basin. , 2011, International journal of systematic and evolutionary microbiology.

[44]  Radhey S. Gupta,et al.  Phylogeny and molecular signatures for the phylum Thermotogae and its subgroups , 2011, Antonie van Leeuwenhoek.

[45]  G. Volckaert,et al.  The kalimantacin/batumin biosynthesis operon encodes a self-resistance isoform of the FabI bacterial target. , 2010, Chemistry & biology.

[46]  R. Müller,et al.  Myxobacterial secondary metabolites: bioactivities and modes-of-action. , 2010, Natural product reports.

[47]  M. Fischbach,et al.  Thirteen posttranslational modifications convert a 14-residue peptide into the antibiotic thiocillin , 2009, Proceedings of the National Academy of Sciences.

[48]  C. Walsh,et al.  Andrimid producers encode an acetyl-CoA carboxyltransferase subunit resistant to the action of the antibiotic , 2008, Proceedings of the National Academy of Sciences.

[49]  P. Glaser,et al.  A Naturally Occurring Gene Amplification Leading to Sulfonamide and Trimethoprim Resistance in Streptococcus agalactiae , 2007, Journal of bacteriology.

[50]  Christopher M Thomas,et al.  Characterization of the mupirocin biosynthesis gene cluster from Pseudomonas fluorescens NCIMB 10586. , 2003, Chemistry & biology.

[51]  R. Gupta,et al.  The phylogeny of proteobacteria: relationships to other eubacterial phyla and eukaryotes. , 2000, FEMS microbiology reviews.

[52]  S. Farrand,et al.  Genetic analysis of agrocin 84 production and immunity in Agrobacterium spp , 1987, Journal of bacteriology.