Glycopeptide antibiotics are produced by Actinobacteria through biosynthetic gene clusters that include genes supporting their regulation, synthesis, export and resistance. The chemical and biosynthetic diversities of glycopeptides are the product of an intricate evolutionary history. Extracting this history from genome sequences is difficult as conservation of the individual components of these gene clusters is variable and each component can have a different trajectory. We show that glycopeptide biosynthesis and resistance in Actinobacteria maps to approximately 150-400 million years ago. Phylogenetic reconciliation reveals that the precursors of glycopeptide biosynthesis are far older than other components, implying that these clusters arose from a pre-existing pool of genes. We find that resistance appeared contemporaneously with biosynthetic genes, raising the possibility that the mechanism of action of glycopeptides was a driver of diversification in these gene clusters. Our results put antibiotic biosynthesis and resistance into an evolutionary context and can guide the future discovery of compounds possessing new mechanisms of action, which are especially needed as the usefulness of the antibiotics available at present is imperilled by human activity.
More details at McMaster’s Brighter World.
Novel gene targets are needed in accurate diagnosis of malaria. Previous studies show that the dynein light chains (dlc) in Plasmodium are uniquely conserved within the species, possibly due to their role as the cargo adptor moiety. This study aimed at the development of PCR assay for the detection of Plasmodium based on the (dlc-Tctex) as a genus and species-specific tool in malaria diagnosis. Multiple primers were designed based on Plasmodium spp dlc(Tctex) genes. The primers were applied on PCR to detect malaria on clinical samples and on laboratory maintained isolates of P. falciparum and P. vivax for human infecting species and P. knowlesi and P. cynomolgi for zoonoses infection involving primates. The amplified PCR fragments were gene cleaned and sequenced. BLASTn e-values output from the raw nucleotide queries supports that the genes are uniquely conserved. Species-specific primers amplified P. falciparum infections with no cross-reactivity to P. vivax, P. knowlesi or P. cynomolgi species. In this assay only 11 out of the 30 microscope positive malaria positive clinical blood samples were positive for PCR detection of P. falciparum infection. Primers designed for Plasmodium genus amplified the target band in all clinical malaria samples but also had another specific band amplification. This preliminary data demonstrate that a species-specific dlc(Tctex) PCR assay can be used for detection of P. falciparum and optimized genus primers can be applied to differentiate mixed malaria infections.
Maguire, F., B. Alcock, A.R. Raphenya, B. Jia. E.J. Griffiths, T.C. Matthews, J. Adam, A. Petkau, G.L. Winsor, IRIDA Consortium, R.G. Beiko, F.S.L. Brinkman, W.W.L. Hsiao. G. Van Domselaar, A.G. McArthur. 2019. Integrated Rapid Infectious Disease Analysis: A comprehensive platform for public health bioinformatics and AMR surveillance using genomic data. Poster presentation at the Canadian Society of Microbiologists Annual Meeting, Sherbrooke, Quebec.
Maguire, F., B. Jia, B. Alcock, A.R. Raphenya, F.S.L. Brinkman, A.G. McArthur, & R.G. Beiko. 2019. Precise identification of antimicrobial resistance determinants from metagenomic data. Oral presentation at the Canadian Society of Microbiologists Annual Meeting, Sherbrooke, Quebec.
Alcock, B.P., A.R. Raphenya, F. Maguire, F.S. Brinkman, R.G. Beiko, & A.G. McArthur. 2019. Resistome and variant prediction for improved antimicrobial surveillance with the Comprehensive Antibiotic Resistance Database. Poster presentation at the American Society for Microbiology Microbe Meeting, San Francisco, California.
Raphenya, A.R., T.T.Y. Lau, B. Alcock, K.K. Tsang, F. Maguire, F.S. Brinkman, R.G. Beiko, & A.G. McArthur. 2019. Resistance Gene Identifier (RGI) – Prediction of antimicrobial resistance genes and mutations for genomic and metagenomic sequencing data. Oral presentation at the American Society for Microbiology Microbe Meeting, San Francisco, California.
Chen, J. C.-Y., C.G. Clark, A. Bharat, A.G. McArthur, M.R. Graham, G.R. Westmacott, & G. Van Domselaar. 2019. Detection of antimicrobial resistance using proteomics and the Comprehensive Antibiotic Resistance Database: A case study. Presentation at 27th Conference on Intelligent Systems in Molecular Biology & 18th European Conference on Computational Biology, Basel, Switzerland.
Tsang, K.K., F. Maguire, H. Zubyk, S. Chou, G.D. Wright, R.G. Beiko, & A.G. McArthur. 2019. Combining multiple features and algorithms to learn antimicrobial resistance genotype-phenotype relationships. Poster presentation at 27th Conference on Intelligent Systems in Molecular Biology & 18th European Conference on Computational Biology, Basel, Switzerland.
Griffiths, E., D. Dooley, G. Gosal, I. Gill, S. Russell, L. Tindale, V. Pichler, T. Matthews, A. Petkau, J. Adam, D. Fornika, G. Winsor, F. Maguire, B. Alcock, The IRIDA Consortium, A.G. McArthur, R. Beiko, M. Graham, F. Brinkman, G. van Domselaar, & W. Hsiao. 2019. Empowering data sharing for genomics-based public health surveillance using ontologies. Presentation at the 12th International Meeting On Epidemiological Markers (IMMEMXII), Dubrovnik, Croatia.
Matthews, T., F. Bristow, A. Petkau, J. Adam, J. Thiessen, S. Sidhu, P. Kruczkiewicz, D. Dooley, E. Griffiths, D. Fornika, G. Winsor, M. Graham, The IRIDA Consortium, A.G. McArthur, E. Taboada, R. Beiko, F. Brinkman, W. Hsiao, & Gary van Domselaar. 2019. Canada’s Integrated Rapid Infectious Disease Analysis Platform (IRIDA). Presentation at the 12th International Meeting On Epidemiological Markers (IMMEMXII), Dubrovnik, Croatia.
Day, E.A., R.J. Ford, B.K. Smith, P. Mohammadi-Shemirani, M.R. Morrow, R.M. Gutgesel, R. Lu, A.R. Raphenya, A.G. McArthur, N. McInnes, G. Paré, H.C. Gerstein, & G.R. Steinberg. 2019. GDF15 is a metformin stimulated hepatokine that is important for promoting weight loss. Presentation at the Lunenfeld-Tanenbaum International Symposium: Translational Diabetes and Metabolism Research Day, Toronto, Ontario.
Griffiths, E., T. Matthews, A. Petkau, J. Adam, D. Dooley, D. Fornika, G. Winsor, F. Maguire, B. Alcock, The IRIDA Consortium, A.G. McArthur, R. Beiko, M. Graham, F. Brinkman, G. van Domselaar, & W. Hsiao. 2019. Empowering local to global WGS-based surveillance and investigation: The Integrated Rapid Infectious Disease Analysis (IRIDA) Platform. Presentation at the Meeting on Global Microbial Identifier, Singapore.
Matthews, T., J. Adam, A. Petkau, F. Maguire, B. Alcock, A.R. Raphenya, E.J. Griffiths, D. Dooley, B. Jia, G.L. Winsor, The IRIDA Consortium, R.G. Beiko, A.G. McArthur, F.S.L. Brinkman, G.L. Van Domselaar, & W.W.L. Hsiao. 2019. Integrated Rapid Infectious Disease Analysis (IRIDA): a comprehensive and distributed platform for public health genomic epidemiology. Poster presentation at the 2019 Applied Bioinformatics and Public Health Microbiology (ABPHM) Meeting, Cambridge, United Kingdom.
Petkau, A., T. Matthews, F. Bristow, J. Adam, J. Thiessen, S. Sidhu, P. Kruczkiewicz, E. Griffiths, D. Dooley, D. Fornika, G. Winsor, M. Graham, A.R. Raphenya, The IRIDA consortium, E. Taboada, A.G. McArthur, R. Beiko, W. Hsiao, F. Brinkman, G. Van Domselaar. 2019. The IRIDA Platform for Microbial Genomics. Oral presentation at the 2019 Galaxy Community Conference, Freiburg, Germany.
Porter, A.F., A.T. Duggan, J. Klunk, E.C. Holmes, H. Poinar, A.N. Dhody, R. Hicks, G. Smith, M. Humpherys, A. McCollum, W. Davidson, K. Wilkins, Y. Li, A. Burke, H. Polasky, L. Flanders, D. Poinar, A.R. Raphenya, B. Alcock, T.T. Lau, A.G. McArthur, & B. Golding. 2019. Unraveling the evolutionary history of the vaccinia virus, the vaccine for smallpox. Presentation at the Annual Meeting of the Society for Molecular Biology and Evolution, Manchester Central, United Kingdom.
Faltyn, M., B. Alcock, & A.G. McArthur. 2019. Evolution and nomenclature of the trimethoprim resistant dihydrofolate (dfr) reductases. Preprints 2019, 2019050137. [Preprint]
Tsang, K.K., D.J. Speicher, & A.G. McArthur. 2019. Pathogen taxonomy updates at the Comprehensive Antibiotic Resistance Database: Implications for molecular epidemiology. Preprints 2019, 2019070222. [Preprint]
Learn about the BDC program here.
David Braley Centre for Antibiotic Discovery gives researchers a fighting chance against antimicrobial resistance.
A forward-looking McMaster donor is investing $7 million in a new research centre dedicated specifically to tackling the growing global threat of antimicrobial resistance.
David Braley, whose gifts to the university include a $50-million investment in McMaster teaching, learning and health-care research and delivery, has allocated $7 million from that 2007 gift towards the new David Braley Centre for Antibiotic Discovery.
The centre will operate from the Michael G. DeGroote Institute for Infectious Disease Research, whose labs and offices are located on campus in the Michael G. DeGroote Centre for Learning and Discovery.
Empowering conventional antibiotics with new drug leads targeting the outer-membrane of Gram-negative pathogens. E. Brown (PI), G.D. Wright (co-I), B. Coombes (co-I), A.G. McArthur (co-I), J. Magolan (co-I), C. Whitfield (co-I, Univ. Guelph). Ontario Research Fund – Research Excellence.
Taking control of antibiotic production: establishing and exploiting a systems-level understanding of antibiotic regulation in the actinobacteria. M. Elliot (PI) & A.G. McArthur (co-I). David Braley Center for Antibiotic Discovery (McMaster) Research Grant.
Dr. McArthur and PhD student Kara Tsang taught together at the 2019 MacData Institute Summer School, with Dr. McArthur reviewing biocuration and bioinformatics for genomic surviellence of antimicrobial resistance and Kara following up with a lecture on machine learning techniques to predict clinical antimicrobial resistance from raw genomic sequence.
Also congratulations to Kara for being awarded a 2019 Faculty of Health Sciences Graduate Programs Excellence Award!
Updated August 6, 2019: Congratulations to Kara for also winning an Ontario Graduate Scholarship!
Welcome to our 2019 Summer students Rachel Tran, Megane Bouchard, and Arman Edalatmand, plus curation volunteers Anna-Lisa Nguyen and William Huynh! Rachel is collaborating with the Whitney lab on evolution of bacterial competition, Megane with the Sloboda & Bowdish labs on ageing and maternal health data harmonization, and Arman on new methods for biocuration of quantitative antimicrobial resistance (AMR) data. Anna-Lisa & William will be working on curation of AMR data in the Comprehensive Antibiotic Resistance Database.
Speicher, D.J., K. Luinstra, J. Maciejewski, K.K. Tsang, A.G. McArthur, & M. Smieja. 2019. Clostridioides difficile strain divergence over time. Oral presentation at the Association of Medical Microbiology and Infectious Disease Canada (AMMI Canada) & Canadian Association for Clinical Microbiology and Infectious Diseases (CACMID) Joint Annual Conference, Ottawa, Ontario.
Background: Clostridioides difficileinfection (CDI) is a serious hospital-associated infection with severe outbreaks caused by the hypervirulent NAP1/MLST-1 strain. Whole genome sequencing has shown that most outbreak strains are clonal whereas non-outbreaks display a wide diversity of strains. To examine strain diversity in clinical settings, a subset of C. difficileisolates from symptomatic CDI from an acute care hospital were compared to isolates from C. difficilecolonized (CDC) asymptomatic subjects from the same hospital.
Methods: A subset of PCR-positive stool samples from clinically confirmed CDI isolates from 2016 (13/110), 2017 (8/111), and 2018 (13/65), and CDC from 2017 (17/185) were cultured 3-times consecutively on CHROMagar™ C. difficile, sub-cultured on Columbia colistin-nalidixic acid (CNA) media, had DNA isolated, shotgun sequenced, and genome assembled for both MLST typing and genome-wide SNP phylogenetic analysis.
Results: Based on MLST profiles, the C. difficiletypes detected were diverse. Of the presumed binary toxin positive/NAP1 strains (i.e. PCR tcdA/tcdBpositive) 7/12 (58%) were NAP1/MLST-1 and 3/12 (25%) were NAP7/MLST-11. NAP1/MLST-1 was not detected in any CDC isolate. NAP4/MLST-2,14 were detected in 2016 (n=4), 2017 (n=2), 2018 (n=1), and in CDC isolates (n=3). MLST-42 was dominant in CDC isolates (5/17; 29%) and decreased in prevalence in CDI isolates over time (2016=4; 2017=0; 2018=1).
Conclusion: C. difficilestrains amongst both CDI and CDC individuals are highly divergent. Whilst molecular assays are misclassifying 25% of “NAP1” strains, both NAP1 and NAP7 are hypervirulent. The number of MLST-42 CDC isolates is concerning as it has been reported to be the most common strain causing CDI among U.S. adults. This highlights the need for continued genomic surveillance of both CDI and CDC individuals. Genome-wide SNP phylogenetic analysis is currently being performed.