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      Predicting antibacterial activity from snake venom proteomes

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          Abstract

          The continued evolution of antibiotic resistance has increased the urgency for new antibiotic development, leading to exploration of non-traditional sources. In particular, snake venom has garnered attention for its potent antibacterial properties. Numerous studies describing snake venom proteomic composition as well as antibiotic efficacy have created an opportunity to synthesize relationships between venom proteomes and their antibacterial properties. Using literature reported values from peer-reviewed studies, our study generated models to predict efficacy given venom protein family composition, snake taxonomic family, bacterial Gram stain, bacterial morphology, and bacterial respiration strategy. We then applied our predictive models to untested snake species with known venom proteomic compositions. Overall, our results provide potential protein families that serve as accurate predictors of efficacy as well as promising organisms in terms of antibacterial properties of venom. The results from this study suggest potential future research trajectories for antibacterial properties in snake venom by offering hypotheses for a variety of taxa.

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          Threshold criteria for conversion of probability of species presence to either–or presence–absence

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            Areas beneath the relative operating characteristics (ROC) and relative operating levels (ROL) curves: Statistical significance and interpretation

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              Evolution of an arsenal: structural and functional diversification of the venom system in the advanced snakes (Caenophidia).

              Venom is a key innovation underlying the evolution of advanced snakes (Caenophidia). Despite this, very little is known about venom system structural diversification, toxin recruitment event timings, or toxin molecular evolution. A multidisciplinary approach was used to examine the diversification of the venom system and associated toxins across the full range of the approximately 100 million-year-old advanced snake clade with a particular emphasis upon families that have not secondarily evolved a front-fanged venom system ( approximately 80% of the 2500 species). Analysis of cDNA libraries revealed complex venom transcriptomes containing multiple toxin types including three finger toxins, cobra venom factor, cysteine-rich secretory protein, hyaluronidase, kallikrein, kunitz, lectin, matrix metalloprotease, phospholipase A(2), snake venom metalloprotease/a disintegrin and metalloprotease, and waprin. High levels of sequence diversity were observed, including mutations in structural and functional residues, changes in cysteine spacing, and major deletions/truncations. Morphological analysis comprising gross dissection, histology, and magnetic resonance imaging also demonstrated extensive modification of the venom system architecture in non-front-fanged snakes in contrast to the conserved structure of the venom system within the independently evolved front-fanged elapid or viperid snakes. Further, a reduction in the size and complexity of the venom system was observed in species in which constriction has been secondarily evolved as the preferred method of prey capture or dietary preference has switched from live prey to eggs or to slugs/snails. Investigation of the timing of toxin recruitment events across the entire advanced snake radiation indicates that the evolution of advanced venom systems in three front-fanged lineages is associated with recruitment of new toxin types or explosive diversification of existing toxin types. These results support the role of venom as a key evolutionary innovation in the diversification of advanced snakes and identify a potential role for non-front-fanged venom toxins as a rich source for lead compounds for drug design and development.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: MethodologyRole: ResourcesRole: SoftwareRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: InvestigationRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: InvestigationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: Project administrationRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                24 January 2020
                2020
                : 15
                : 1
                : e0226807
                Affiliations
                [1 ] Department of Biology, University of Findlay, Findlay, Ohio, United States of America
                [2 ] School of the Environment, Washington State University, Pullman, Washington, United States of America
                Instituto Butantan, BRAZIL
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                ‡ These authors also contributed equally to this work.

                Author information
                http://orcid.org/0000-0002-6354-7164
                http://orcid.org/0000-0002-8034-9434
                http://orcid.org/0000-0002-1885-1490
                Article
                PONE-D-19-04720
                10.1371/journal.pone.0226807
                6980403
                31978103
                0b28aa63-34d5-468f-857f-5c3b3f91ffb7
                © 2020 Rheubert et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 17 February 2019
                : 4 December 2019
                Page count
                Figures: 5, Tables: 0, Pages: 18
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100008982, National Science Foundation;
                Award ID: DGE-1347973
                Award Recipient :
                This work was supported by the National Science Foundation Graduate Research Fellowship, NSFDGE-1347973 ( https://www.nsf.gov/) to MFM. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Toxicology
                Toxic Agents
                Toxins
                Venoms
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Toxicology
                Toxic Agents
                Toxins
                Venoms
                Medicine and Health Sciences
                Pharmacology
                Drugs
                Antimicrobials
                Antibacterials
                Biology and Life Sciences
                Microbiology
                Microbial Control
                Antimicrobials
                Antibacterials
                Biology and Life Sciences
                Organisms
                Bacteria
                Anaerobic Bacteria
                Biology and Life Sciences
                Organisms
                Eukaryota
                Animals
                Vertebrates
                Amniotes
                Reptiles
                Squamates
                Snakes
                Biology and Life Sciences
                Organisms
                Bacteria
                Bacillus
                Biology and Life Sciences
                Microbiology
                Medical Microbiology
                Microbial Pathogens
                Bacterial Pathogens
                Bacillus
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Pathogens
                Microbial Pathogens
                Bacterial Pathogens
                Bacillus
                Biology and Life Sciences
                Microbiology
                Bacteriology
                Gram Positive Bacteria
                Biology and Life Sciences
                Microbiology
                Bacteriology
                Gram Negative Bacteria
                Biology and Life Sciences
                Biochemistry
                Proteins
                Proteomes
                Custom metadata
                An accompanying technical document as well as raw data, aggregated data, and R scripts are available to assist in future implementation of these methods (Meyer MF, Rheubert JL, Charvat R, 2018. Predicting antibacterial activity from snake venom proteomes [WWW Document]. URL: osf.io/3yxjt.

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