Nerpa: A Tool for Discovering Biosynthetic Gene Clusters of Bacterial Nonribosomal Peptides

Kunyavskaya, Olga; Tagirdzhanov, Azat M.; Caraballo-Rodríguez, Andrés Mauricio; Nothias, Louis-Félix; Dorrestein, Pieter C.; Korobeynikov, Anton; Mohimani, Hosein; Gurevich, Alexey

doi:10.3390/metabo11100693

Title: Nerpa: A Tool for Discovering Biosynthetic Gene Clusters of Bacterial Nonribosomal Peptides

Abstract

Microbial natural products are a major source of bioactive compounds for drug discovery. Among these molecules, nonribosomal peptides (NRPs) represent a diverse class of natural products that include antibiotics, immunosuppressants, and anticancer agents. Recent breakthroughs in natural product discovery have revealed the chemical structure of several thousand NRPs. However, biosynthetic gene clusters (BGCs) encoding them are known only for a few hundred compounds. Here, we developed Nerpa, a computational method for the high-throughput discovery of novel BGCs responsible for producing known NRPs. After searching 13,399 representative bacterial genomes from the RefSeq repository against 8368 known NRPs, Nerpa linked 117 BGCs to their products. We further experimentally validated the predicted BGC of ngercheumicin from Photobacterium galatheae via mass spectrometry. Nerpa supports searching new genomes against thousands of known NRP structures, and novel molecular structures against tens of thousands of bacterial genomes. The availability of these tools can enhance our understanding of NRP synthesis and the function of their biosynthetic enzymes.

Authors:

;

Publication Date:: Mon Oct 11 00:00:00 EDT 2021

Research Org.:: Carnegie Mellon Univ., Pittsburgh, PA (United States)

Sponsoring Org.:: USDOE Office of Science (SC); Russian Foundation for Basic Research (RFBR); Alfred P. Sloan Foundation; National Institutes of Health (NIH); National Science Foundation (NSF); Gordon and Betty Moore Foundation

OSTI Identifier:: 1825143

Alternate Identifier(s):: OSTI ID: 1981161

Grant/Contract Number:: SC0021340; DP2GM137413; DBI2117640; GBMF7622; P41 GM103484; R01 GM107550; 1DP2GM137413-01

Resource Type:: Published Article

Journal Name:: Metabolites

Additional Journal Information:: Journal Name: Metabolites Journal Volume: 11 Journal Issue: 10; Journal ID: ISSN 2218-1989

Publisher:: MDPI AG

Country of Publication:: Switzerland

Language:: English

Subject:: 59 BASIC BIOLOGICAL SCIENCES; natural products; nonribosomal peptides; genome mining; biosynthetic gene clusters; bioinformatics; mass spectrometry; software; machine learning

Citation Formats


                    Kunyavskaya, Olga, Tagirdzhanov, Azat M., Caraballo-Rodríguez, Andrés Mauricio, Nothias, Louis-Félix, Dorrestein, Pieter C., Korobeynikov, Anton, Mohimani, Hosein, and Gurevich, Alexey. Nerpa: A Tool for Discovering Biosynthetic Gene Clusters of Bacterial Nonribosomal Peptides.  Switzerland: N. p., 2021. 
Web.  doi:10.3390/metabo11100693.

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                    Kunyavskaya, Olga, Tagirdzhanov, Azat M., Caraballo-Rodríguez, Andrés Mauricio, Nothias, Louis-Félix, Dorrestein, Pieter C., Korobeynikov, Anton, Mohimani, Hosein, & Gurevich, Alexey. Nerpa: A Tool for Discovering Biosynthetic Gene Clusters of Bacterial Nonribosomal Peptides.  Switzerland.  https://doi.org/10.3390/metabo11100693

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                    Kunyavskaya, Olga, Tagirdzhanov, Azat M., Caraballo-Rodríguez, Andrés Mauricio, Nothias, Louis-Félix, Dorrestein, Pieter C., Korobeynikov, Anton, Mohimani, Hosein, and Gurevich, Alexey. Mon .  
"Nerpa: A Tool for Discovering Biosynthetic Gene Clusters of Bacterial Nonribosomal Peptides".  Switzerland.  https://doi.org/10.3390/metabo11100693.

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@article{osti_1825143,

  title        = {Nerpa: A Tool for Discovering Biosynthetic Gene Clusters of Bacterial Nonribosomal Peptides},

  author       = {Kunyavskaya, Olga and Tagirdzhanov, Azat M. and Caraballo-Rodríguez, Andrés Mauricio and Nothias, Louis-Félix and Dorrestein, Pieter C. and Korobeynikov, Anton and Mohimani, Hosein and Gurevich, Alexey},

  abstractNote = {Microbial natural products are a major source of bioactive compounds for drug discovery. Among these molecules, nonribosomal peptides (NRPs) represent a diverse class of natural products that include antibiotics, immunosuppressants, and anticancer agents. Recent breakthroughs in natural product discovery have revealed the chemical structure of several thousand NRPs. However, biosynthetic gene clusters (BGCs) encoding them are known only for a few hundred compounds. Here, we developed Nerpa, a computational method for the high-throughput discovery of novel BGCs responsible for producing known NRPs. After searching 13,399 representative bacterial genomes from the RefSeq repository against 8368 known NRPs, Nerpa linked 117 BGCs to their products. We further experimentally validated the predicted BGC of ngercheumicin from Photobacterium galatheae via mass spectrometry. Nerpa supports searching new genomes against thousands of known NRP structures, and novel molecular structures against tens of thousands of bacterial genomes. The availability of these tools can enhance our understanding of NRP synthesis and the function of their biosynthetic enzymes.},

  doi          = {10.3390/metabo11100693},

  journal      = {Metabolites},

  number       = 10,

  volume       = 11,

  place        = {Switzerland},

  year         = {Mon Oct 11 00:00:00 EDT 2021},

  month        = {Mon Oct 11 00:00:00 EDT 2021}

}

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Abstract

Citation Formats

Polyketide and nonribosomal peptide retro-biosynthesis and global gene cluster matching journal, October 2016

NRPquest: Coupling Mass Spectrometry and Genome Mining for Nonribosomal Peptide Discovery journal, August 2014

Minimum Information about a Biosynthetic Gene cluster journal, August 2015

Specificity prediction of adenylation domains in nonribosomal peptide synthetases (NRPS) using transductive support vector machines (TSVMs) journal, October 2005

More than Anticipated – Production of Antibiotics and Other Secondary Metabolites by Bacillus amyloliquefaciens FZB42 journal, January 2009

Modular Peptide Synthetases Involved in Nonribosomal Peptide Synthesis journal, November 1997

Dereplication of microbial metabolites through database search of mass spectra journal, October 2018

A machine learning-based method for prediction of macrocyclization patterns of polyketides and non-ribosomal peptides journal, November 2020

Phylogenetic analysis of condensation domains in NRPS sheds light on their functional evolution journal, January 2007

SANDPUMA: ensemble predictions of nonribosomal peptide chemistry reveal biosynthetic diversity across Actinobacteria journal, June 2017

Biosynthetic Pathway for Mannopeptimycins, Lipoglycopeptide Antibiotics Active against Drug-Resistant Gram-Positive Pathogens journal, June 2006

Characterization of the Ohmyungsamycin Biosynthetic Pathway and Generation of Derivatives with Improved Antituberculosis Activity journal, October 2019

Bacterial Biosynthesis and Maturation of the Didemnin Anti-cancer Agents journal, April 2012

Structure and Biosynthesis of Amychelin, an Unusual Mixed-Ligand Siderophore from Amycolatopsis sp. AA4 journal, July 2011

Comprehensive prediction of secondary metabolite structure and biological activity from microbial genome sequences journal, November 2020

RiPPMiner: a bioinformatics resource for deciphering chemical structures of RiPPs based on prediction of cleavage and cross-links journal, May 2017

An Iterative Nonribosomal Peptide Synthetase Assembles the Pyrrole-Amide Antibiotic Congocidine in Streptomyces ambofaciens journal, April 2009

Dereplication of peptidic natural products through database search of mass spectra journal, October 2016

Pep2Path: Automated Mass Spectrometry-Guided Genome Mining of Peptidic Natural Products journal, September 2014

StreptomeDB 3.0: an updated compendium of streptomycetes natural products journal, October 2020

Cracking the Nonribosomal Code journal, May 2016

Learning from Nature's Drug Factories: Nonribosomal Synthesis of Macrocyclic Peptides journal, December 2003

antiSMASH 2.0—a versatile platform for genome mining of secondary metabolite producers journal, May 2013

The specificity-conferring code of adenylation domains in nonribosomal peptide synthetases journal, August 1999

antiSMASH: rapid identification, annotation and analysis of secondary metabolite biosynthesis gene clusters in bacterial and fungal genome sequences journal, June 2011

antiSMASH 4.0—improvements in chemistry prediction and gene cluster boundary identification journal, April 2017

Identification of Four New agr Quorum Sensing-Interfering Cyclodepsipeptides from a Marine Photobacterium journal, December 2013

Interactive metagenomic visualization in a Web browser journal, September 2011

The antiSMASH database version 3: increased taxonomic coverage and new query features for modular enzymes journal, November 2020

Photobacterium galatheae sp. nov., a bioactive bacterium isolated from a mussel in the Solomon Sea journal, December 2015

Assembly-Line Enzymology for Polyketide and Nonribosomal Peptide Antibiotics: Logic, Machinery, and Mechanisms journal, August 2006

rBAN: retro-biosynthetic analysis of nonribosomal peptides journal, February 2019

NCBI Reference Sequence (RefSeq): a curated non-redundant sequence database of genomes, transcripts and proteins journal, December 2004

MIBiG 2.0: a repository for biosynthetic gene clusters of known function journal, October 2019

Discovery of Antimicrobial Lipodepsipeptides Produced by a Serratia sp. within Mosquito Microbiomes journal, June 2018

On the Antibacterial Action of Cultures of a Penicillium, with Special Reference to Their Use in the Isolation of B. influenzae journal, January 1980

Automated genome mining for natural products journal, January 2009

Nonribosomal Peptide Synthesis-Principles and Prospects journal, March 2017

Nonribosomal Peptides from Marine Microbes and Their Antimicrobial and Anticancer Potential journal, November 2017

Sharing and community curation of mass spectrometry data with Global Natural Products Social Molecular Networking journal, August 2016

Increased diversity of peptidic natural products revealed by modification-tolerant database search of mass spectra journal, January 2018

Norine, the knowledgebase dedicated to non-ribosomal peptides, is now open to crowdsourcing journal, November 2015

A general method applicable to the search for similarities in the amino acid sequence of two proteins journal, March 1970

Ohmyungsamycins A and B: Cytotoxic and Antimicrobial Cyclic Peptides Produced by Streptomyces sp. from a Volcanic Island journal, November 2013

antiSMASH 5.0: updates to the secondary metabolite genome mining pipeline journal, April 2019

Characterization of the colistin (polymyxin E1 and E2) biosynthetic gene cluster journal, January 2015

Genomic charting of ribosomally synthesized natural product chemical space facilitates targeted mining journal, October 2016

SeMPI 2.0—A Web Server for PKS and NRPS Predictions Combined with Metabolite Screening in Natural Product Databases journal, December 2020

PubChem Substance and Compound databases journal, September 2015

NRPSpredictor2—a web server for predicting NRPS adenylation domain specificity journal, May 2011

antiSMASH 3.0—a comprehensive resource for the genome mining of biosynthetic gene clusters journal, May 2015

The Natural Products Atlas: An Open Access Knowledge Base for Microbial Natural Products Discovery journal, September 2019

Biosynthesis of the cyclooligomer depsipeptide bassianolide, an insecticidal virulence factor of Beauveria bassiana journal, May 2009

Selective interaction between nonribosomal peptide synthetases is facilitated by short communication-mediating domains journal, October 2004

Seven More Microcystins from Homer Lake Cells: Application of the General Method for Structure Assignment of Peptides Containing .alpha.,.beta.-Dehydroamino Acid Unit(s) journal, June 1995

Polyketide and nonribosomal peptide retro-biosynthesis and global gene cluster matching
journal, October 2016

NRPquest: Coupling Mass Spectrometry and Genome Mining for Nonribosomal Peptide Discovery
journal, August 2014

Minimum Information about a Biosynthetic Gene cluster
journal, August 2015

Specificity prediction of adenylation domains in nonribosomal peptide synthetases (NRPS) using transductive support vector machines (TSVMs)
journal, October 2005

More than Anticipated – Production of Antibiotics and Other Secondary Metabolites by Bacillus amyloliquefaciens FZB42
journal, January 2009

Modular Peptide Synthetases Involved in Nonribosomal Peptide Synthesis
journal, November 1997

Dereplication of microbial metabolites through database search of mass spectra
journal, October 2018

A machine learning-based method for prediction of macrocyclization patterns of polyketides and non-ribosomal peptides
journal, November 2020

Phylogenetic analysis of condensation domains in NRPS sheds light on their functional evolution
journal, January 2007

SANDPUMA: ensemble predictions of nonribosomal peptide chemistry reveal biosynthetic diversity across Actinobacteria
journal, June 2017

Biosynthetic Pathway for Mannopeptimycins, Lipoglycopeptide Antibiotics Active against Drug-Resistant Gram-Positive Pathogens
journal, June 2006

Characterization of the Ohmyungsamycin Biosynthetic Pathway and Generation of Derivatives with Improved Antituberculosis Activity
journal, October 2019

Bacterial Biosynthesis and Maturation of the Didemnin Anti-cancer Agents
journal, April 2012

Structure and Biosynthesis of Amychelin, an Unusual Mixed-Ligand Siderophore from Amycolatopsis sp. AA4
journal, July 2011

Comprehensive prediction of secondary metabolite structure and biological activity from microbial genome sequences
journal, November 2020

RiPPMiner: a bioinformatics resource for deciphering chemical structures of RiPPs based on prediction of cleavage and cross-links
journal, May 2017

An Iterative Nonribosomal Peptide Synthetase Assembles the Pyrrole-Amide Antibiotic Congocidine in Streptomyces ambofaciens
journal, April 2009

Dereplication of peptidic natural products through database search of mass spectra
journal, October 2016

Pep2Path: Automated Mass Spectrometry-Guided Genome Mining of Peptidic Natural Products
journal, September 2014

StreptomeDB 3.0: an updated compendium of streptomycetes natural products
journal, October 2020

Cracking the Nonribosomal Code
journal, May 2016

Learning from Nature's Drug Factories: Nonribosomal Synthesis of Macrocyclic Peptides
journal, December 2003

antiSMASH 2.0—a versatile platform for genome mining of secondary metabolite producers
journal, May 2013

The specificity-conferring code of adenylation domains in nonribosomal peptide synthetases
journal, August 1999

antiSMASH: rapid identification, annotation and analysis of secondary metabolite biosynthesis gene clusters in bacterial and fungal genome sequences
journal, June 2011

antiSMASH 4.0—improvements in chemistry prediction and gene cluster boundary identification
journal, April 2017

Identification of Four New agr Quorum Sensing-Interfering Cyclodepsipeptides from a Marine Photobacterium
journal, December 2013

Interactive metagenomic visualization in a Web browser
journal, September 2011

The antiSMASH database version 3: increased taxonomic coverage and new query features for modular enzymes
journal, November 2020

Photobacterium galatheae sp. nov., a bioactive bacterium isolated from a mussel in the Solomon Sea
journal, December 2015

Assembly-Line Enzymology for Polyketide and Nonribosomal Peptide Antibiotics: Logic, Machinery, and Mechanisms
journal, August 2006

rBAN: retro-biosynthetic analysis of nonribosomal peptides
journal, February 2019

NCBI Reference Sequence (RefSeq): a curated non-redundant sequence database of genomes, transcripts and proteins
journal, December 2004

MIBiG 2.0: a repository for biosynthetic gene clusters of known function
journal, October 2019

Discovery of Antimicrobial Lipodepsipeptides Produced by a Serratia sp. within Mosquito Microbiomes
journal, June 2018

On the Antibacterial Action of Cultures of a Penicillium, with Special Reference to Their Use in the Isolation of B. influenzae
journal, January 1980

Automated genome mining for natural products
journal, January 2009

Nonribosomal Peptide Synthesis-Principles and Prospects
journal, March 2017

Nonribosomal Peptides from Marine Microbes and Their Antimicrobial and Anticancer Potential
journal, November 2017

Sharing and community curation of mass spectrometry data with Global Natural Products Social Molecular Networking
journal, August 2016

Increased diversity of peptidic natural products revealed by modification-tolerant database search of mass spectra
journal, January 2018

Norine, the knowledgebase dedicated to non-ribosomal peptides, is now open to crowdsourcing
journal, November 2015

A general method applicable to the search for similarities in the amino acid sequence of two proteins
journal, March 1970

Ohmyungsamycins A and B: Cytotoxic and Antimicrobial Cyclic Peptides Produced by Streptomyces sp. from a Volcanic Island
journal, November 2013

antiSMASH 5.0: updates to the secondary metabolite genome mining pipeline
journal, April 2019

Characterization of the colistin (polymyxin E1 and E2) biosynthetic gene cluster
journal, January 2015

Genomic charting of ribosomally synthesized natural product chemical space facilitates targeted mining
journal, October 2016

SeMPI 2.0—A Web Server for PKS and NRPS Predictions Combined with Metabolite Screening in Natural Product Databases
journal, December 2020

PubChem Substance and Compound databases
journal, September 2015

NRPSpredictor2—a web server for predicting NRPS adenylation domain specificity
journal, May 2011

antiSMASH 3.0—a comprehensive resource for the genome mining of biosynthetic gene clusters
journal, May 2015

The Natural Products Atlas: An Open Access Knowledge Base for Microbial Natural Products Discovery
journal, September 2019

Biosynthesis of the cyclooligomer depsipeptide bassianolide, an insecticidal virulence factor of Beauveria bassiana
journal, May 2009

Selective interaction between nonribosomal peptide synthetases is facilitated by short communication-mediating domains
journal, October 2004

Seven More Microcystins from Homer Lake Cells: Application of the General Method for Structure Assignment of Peptides Containing .alpha.,.beta.-Dehydroamino Acid Unit(s)
journal, June 1995