In silico tools for the analysis of antibiotic biosynthetic pathways.

Natural products of bacteria and fungi are the most important source for antimicrobial drug leads. For decades, such compounds were exclusively found by chemical/bioactivity-guided screening approaches. The rapid progress in sequencing technologies only recently allowed the development of novel screening methods based on the genome sequences of potential producing organisms. The basic principle of such genome mining approaches is to identify genes, which are involved in the biosynthesis of such molecules, and to predict the products of the identified pathways. Thus, bioinformatics methods and tools are crucial for genome mining. In this review, a comprehensive overview is given on programs and databases for the identification and analysis of antibiotic biosynthesis gene clusters in genomic data.

[1]  Michael A Fischbach,et al.  Natural products version 2.0: connecting genes to molecules. , 2010, Journal of the American Chemical Society.

[2]  G. Challis,et al.  Predictive, structure-based model of amino acid recognition by nonribosomal peptide synthetase adenylation domains. , 2000, Chemistry & biology.

[3]  Gitanjali Yadav,et al.  SBSPKS: structure based sequence analysis of polyketide synthases , 2010, Nucleic Acids Res..

[4]  János Bérdy,et al.  Bioactive microbial metabolites. , 2005, The Journal of antibiotics.

[5]  Mikael R. Andersen,et al.  Accurate prediction of secondary metabolite gene clusters in filamentous fungi , 2012, Proceedings of the National Academy of Sciences.

[6]  J. Martín,et al.  Cloning and Expression of Antibiotic Production Genes , 1984, Bio/Technology.

[7]  Kai Blin,et al.  antiSMASH 2.0—a versatile platform for genome mining of secondary metabolite producers , 2013, Nucleic Acids Res..

[8]  Sean R. Eddy,et al.  Profile hidden Markov models , 1998, Bioinform..

[9]  Kai Blin,et al.  antiSMASH: rapid identification, annotation and analysis of secondary metabolite biosynthesis gene clusters in bacterial and fungal genome sequences , 2011, Nucleic Acids Res..

[10]  E. Myers,et al.  Basic local alignment search tool. , 1990, Journal of molecular biology.

[11]  Gitanjali Yadav,et al.  NRPS-PKS: a knowledge-based resource for analysis of NRPS/PKS megasynthases , 2004, Nucleic Acids Res..

[12]  Kazuki Saito,et al.  KNApSAcK family databases: integrated metabolite-plant species databases for multifaceted plant research. , 2012, Plant & cell physiology.

[13]  Gregory Kucherov,et al.  NORINE: a database of nonribosomal peptides , 2007, Nucleic Acids Res..

[14]  Minoru Kanehisa,et al.  Comprehensive analysis of distinctive polyketide and nonribosomal peptide structural motifs encoded in microbial genomes. , 2007, Journal of molecular biology.

[15]  I. Hoof,et al.  CLUSEAN: a computer-based framework for the automated analysis of bacterial secondary metabolite biosynthetic gene clusters. , 2009, Journal of biotechnology.

[16]  Jurica Zucko,et al.  Predicting substrate specificity of adenylation domains of nonribosomal peptide synthetases and other protein properties by latent semantic indexing , 2013, Journal of Industrial Microbiology & Biotechnology.

[17]  Peter Man-Un Ung,et al.  Automated genome mining for natural products , 2009, BMC Bioinformatics.

[18]  Kiejung Park,et al.  ASMPKS: an analysis system for modular polyketide synthases , 2007, BMC Bioinformatics.

[19]  Oscar P. Kuipers,et al.  BAGEL2: mining for bacteriocins in genomic data , 2010, Nucleic Acids Res..

[20]  Matthew R. Pocock,et al.  The Bioperl toolkit: Perl modules for the life sciences. , 2002, Genome research.

[21]  Thomas L. Madden,et al.  Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. , 1997, Nucleic acids research.

[22]  C. Hertweck,et al.  The biosynthetic logic of polyketide diversity. , 2009, Angewandte Chemie.

[23]  J. Zucko,et al.  Databases of the thiotemplate modular systems (CSDB) and their in silico recombinants (r-CSDB) , 2013, Journal of Industrial Microbiology & Biotechnology.

[24]  Rajesh S. Gokhale,et al.  SEARCHGTr: a program for analysis of glycosyltransferases involved in glycosylation of secondary metabolites , 2005, Nucleic Acids Res..

[25]  Gitanjali Yadav,et al.  Computational approach for prediction of domain organization and substrate specificity of modular polyketide synthases. , 2003, Journal of molecular biology.

[26]  Gwan-Su Yi,et al.  PKMiner: a database for exploring type II polyketide synthases , 2012, BMC Microbiology.

[27]  Kyle R. Conway,et al.  ClusterMine360: a database of microbial PKS/NRPS biosynthesis , 2012, Nucleic Acids Res..

[28]  Kiejung Park,et al.  Development of an analysis program of type I polyketide synthase gene clusters using homology search and profile hidden Markov model. , 2009, Journal of microbiology and biotechnology.

[29]  Kiyoshi Asai,et al.  MIDDAS-M: Motif-Independent De Novo Detection of Secondary Metabolite Gene Clusters through the Integration of Genome Sequencing and Transcriptome Data , 2013, PloS one.

[30]  Carlos Prieto,et al.  NRPSsp: non-ribosomal peptide synthase substrate predictor , 2012, Bioinform..

[31]  Jacques Ravel,et al.  Chapter 8. Methods for in silico prediction of microbial polyketide and nonribosomal peptide biosynthetic pathways from DNA sequence data. , 2009, Methods in enzymology.

[32]  J. Zucko,et al.  Recombinatorial biosynthesis of polyketides , 2011, Journal of Industrial Microbiology & Biotechnology.

[33]  T. Stachelhaus,et al.  The specificity-conferring code of adenylation domains in nonribosomal peptide synthetases. , 1999, Chemistry & biology.

[34]  D. Haft,et al.  SMURF: Genomic mapping of fungal secondary metabolite clusters. , 2010, Fungal genetics and biology : FG & B.

[35]  Christian Senger,et al.  StreptomeDB: a resource for natural compounds isolated from Streptomyces species , 2012, Nucleic Acids Res..

[36]  Nobuyuki Fujita,et al.  DoBISCUIT: a database of secondary metabolite biosynthetic gene clusters , 2012, Nucleic Acids Res..

[37]  Mallika Vijayan,et al.  PKSIIIexplorer: TSVM approach for predicting Type III polyketide synthase proteins , 2011, Bioinformation.

[38]  Tilmann Weber,et al.  Specificity prediction of adenylation domains in nonribosomal peptide synthetases (NRPS) using transductive support vector machines (TSVMs) , 2005, Nucleic acids research.

[39]  Thomas Wolf,et al.  Motif-Based Method for the Genome-Wide Prediction of Eukaryotic Gene Clusters , 2013, ICIAP Workshops.

[40]  S. Bruner,et al.  Structure and noncanonical chemistry of nonribosomal peptide biosynthetic machinery. , 2012, Natural product reports.

[41]  J. Badger,et al.  The Natural Product Domain Seeker NaPDoS: A Phylogeny Based Bioinformatic Tool to Classify Secondary Metabolite Gene Diversity , 2012, PloS one.

[42]  J. Zucko,et al.  ClustScan: an integrated program package for the semi-automatic annotation of modular biosynthetic gene clusters and in silico prediction of novel chemical structures , 2008, Nucleic acids research.

[43]  Gitanjali Yadav,et al.  SEARCHPKS: a program for detection and analysis of polyketide synthase domains , 2003, Nucleic Acids Res..

[44]  Oscar P. Kuipers,et al.  BAGEL: a web-based bacteriocin genome mining tool , 2006, Nucleic Acids Res..

[45]  Oscar P. Kuipers,et al.  BAGEL3: automated identification of genes encoding bacteriocins and (non-)bactericidal posttranslationally modified peptides , 2013, Nucleic Acids Res..

[46]  Oliver Kohlbacher,et al.  Combining Structure and Sequence Information Allows Automated Prediction of Substrate Specificities within Enzyme Families , 2010, PLoS Comput. Biol..

[47]  Kai Blin,et al.  NRPSpredictor2—a web server for predicting NRPS adenylation domain specificity , 2011, Nucleic Acids Res..

[48]  Marnix H Medema,et al.  Bioinformatics approaches and software for detection of secondary metabolic gene clusters. , 2012, Methods in molecular biology.