Iddo Friedberg, PhD Bioinformatics and Computational Biology Iowa State University @iddux Finding Bacteriocins using BOA
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Iddo Friedberg, PhDBioinformatics and Computational Biology
Iowa State University
@iddux
Finding Bacteriocins using BOA
Antibiotic resistanceWHO (2014): “A problem so serious that it threatens the achievements of modern medicine... A post-antibiotic era, in which common infections and minor injuries can kill, far from being an apocalyptic fantasy, is instead a very real possibility for the 21st century.”
Antibiotic Resistance
Nature Chemical Biology 3, 541 - 548 (2007)
Decline in Antiobiotic Approval
Avoiding antbiotic resistance
● Using less antibiotics● Narrow-spectrum
drugs● Harvest more
natural compounds
The Wide World of Bacteriocins
Antimicrobial Peptides
Nisin A
Microcin B17
Berninamycin A
Microcin J25
Bacteriocin AS-48
Virulence Factors
Streptolysin SListeriolysin SClostridiolysin S
CylLL + CylLS
Signaling Peptides
RNPP/Rgg
Agr
Gly-Gly
Bacteriocins AntibioticsSynthesis Ribosomal Secondary metabolite
Bioactivity spectra Mostly narrow Mostly broad
Intensity of bioactivity
Active at nano-to-micro molar range
Active at micro-to-milli molar range
Proteolytic enzyme degradability
High Moderate-to-none
Thermal stability High Low
Active pH range Wide Narrow
Possible mechanism of target cell developing resistance
Adaptation through changes in cell membrane composition
Genetically transferable determinant that inactivates the active compound
Mode of action Pore formation, inhibition of cell wall biosynthesis
Cell membrane or intercellular targets, inhibition cell wall biosynthesis
A B T C I P R K F E G
A B T C I P R K F E G
A B T C I P R K F E G
NisB
NisC
NisT
NisP
A B T C I P R K F E G
NisB
NisC
NisT
NisP
A B T C I P R K F E G
NisB
NisC
NisT
NisP
A B T C I P R K F E G
NisB
NisC
NisT
NisP
A B T C I P R K F E G
NisB
NisC
NisT
NisP
NisF
NisF
NisE
NisG
NisI
A B T C I P R K F E G
NisB
NisC
NisT
NisP
NisF
NisF
NisE
NisG
NisI
NisK
NisR
A B T C I P R K F E G
NisB
NisC
NisT
NisP
NisF
NisF
NisE
NisG
NisI
NisK
NisR
A B T C I P R K F E G
NisB
NisC
NisT
NisP
NisF
NisF
NisE
NisG
NisI
NisK
NisR
Looking for more bacteriocins
Looking for more bacteriocins
?
Bacteriocins may not be homologous, or even detectable as ORFs
So how do we find more bacteriocins?
Antimicrobial Peptides
Nisin A
Microcin B17
Berninamycin A
Microcin J25
Bacteriocin AS-48
Virulence Factors
Streptolysin SListeriolysin SClostridiolysin S
CylLL + CylLS
Signaling Peptides
RNPP/Rgg
Agr
Gly-Gly
?
Use the homologs we have: genomic-context
BOA
Bacteriocin Operon Associator
LC-Set BAGEL BOA
Bacteriocin Operon Associator
LC-Set BAGEL
BLAST vs. GenBank
BOA
Bacteriocin Operon Associator
LC-Set BAGEL
BLAST vs. GenBank
Within 50kb of toxin gene
BOA
Bacteriocin Operon Associator
LC-Set BAGEL
BLAST vs. GenBank
Within 50kb of toxin gene
pHMM
HMMER
pHMM pHMM pHMM pHMM
BOA
Bacteriocin Operon Associator
LC-Set BAGEL
BLAST vs. GenBank
Within 50kb of toxin gene
pHMM
HMMER
pHMM pHMM pHMM pHMM
Clique Filter
BOA
Bacteriocin Operon Associator
The Clique Filter
Approving cliques
Yes
No
The Clique Filter
BAGEL v. BOA
Gene Blocks Found
Method Found
BAGEL 453
BOA + Toxin genes 1,003
BOA – Toxin genes 83
Top 3 Genomes: Different EcosystemsStreptococcus equi Streptomyces griseus Leifsonia xyli
Summing Up
● Annotated genbank files with all predicted bacteriocin blocks are available
● Need more curated bacteriocin blocks for training● Explore use of feature vectors with different
combinations / weights of context genes● Feed into experiments ← → and back● https://github.com/idoerg/BOA● Paper & data in production BMC Bioinformatics● http://arxiv.org/abs/1510.06008
Thanks
Jamie Morton
Stefan Freed Shaun Lee
Bioinformatics & Computational Biology PhD Program
● Well-established program, since 2000● Strengths in: genomics, structural bioinformatics, evolution,
bioengineering● NSF Training grant in plant phenomics● $$$ from: Graduate College, Vice Provost Presidential Initiative
Fellowships; Students take part in major plant and pharmaceutical company internships
● Recent Big Data presidential initiative faculty hires in metagenomics, phylogenetics, protein function prediction & more.
● Apply by February 15
Join the Friedberg Lab
http://iddo-friedberg.net
Biosynthesis of Bacteriocins
Gabrielsen et al. J. Bacteriol. 2014;196:911-919
Streptococcus equi 6
Streptomyces griseus 6
Lefsonia xyli 5
Pusillimonas sp. 4
Rhodosprillum rubrum 4
Streptococcus salivarius
4
Stretomyces sp. 4
Streptomyces pratensis
4
Symbiobacterium thermophilum
4
Thermotoga neopolitana
4
Sterptococcus equi (8)
Biosynthesis of Bacteriocins
Gabrielsen et al. J. Bacteriol. 2014;196:911-919
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