Congratulations to our 3rd year Biochemistry & Biomedical Sciences students upon completion of their research projects! Both will be staying on as summer research students.
Tammy Lau – The Importance of Protocol Design for RNA-Seq in the Ongoing Development of a Novel Technology for Tissue Specific Gene Expression Profiling in C. elegans
Arjun Sharma – The Glycopeptide Resistance Predictor
Suman Virdee – Developing a Galaxy based Pipeline for RNA-Seq Analysis in Stem Cell Biology
Kirill Pankov – The Cytochrome P450 (CYP) Superfamily in the Cnidarian Phylum
Jonsson Liu – Clinical virulence detection and Clostridium difficile clonality
Annie Cheng – Predicting Plasmid-Mediated Antimicrobial Resistance from Whole Genome Sequencing
Godwin Chan – Using the Galaxy Platform to Increase Accessibility for Structure Determination via Cryo-Electron Microscopy
Congratulations to 4th Year Biomedical Discovery & Commercialization student and McArthur lab member Suman Virdee for her CIHR Undergraduate Summer Studentship Award for her summer project “Development and implementation of computational tools to dissect cancer stem cell circuitry”, a joint project between our laboratory and that of Dr. Kristin Hope!
Type III Secretion Systems (T3SSs) are structurally conserved nanomachines that span the inner and outer bacterial membranes, and via a protruding needle complex contact host cell membranes and deliver type III effector proteins. T3SS are phylogenetically divided into several families based on structural basal body components. Here we have studied the evolutionary and functional conservation of four T3SS proteins from the Inv/Mxi-Spa family: a cytosolic chaperone, two hydrophobic translocators that form a plasma membrane-integral pore, and the hydrophilic ‘tip complex’ translocator that connects the T3SS needle to the translocon pore. Salmonella enterica serovar Typhimurium (S. Typhimurium), a common cause of food-borne gastroenteritis, possesses two T3SSs, one belonging to the Inv/Mxi-Spa family. We used invasion-deficient S. Typhimurium mutants as surrogates for expression of translocator orthologs identified from an extensive phylogenetic analysis, and type III effector translocation and host cell invasion as a readout for complementation efficiency, and identified several Inv/Mxi-Spa orthologs that can functionally substitute for the S. Typhimurium chaperone and translocator proteins. Functional complementation correlates with amino acid sequence identity between orthologs, but varies considerably between the four proteins. This is the first in-depth survey of the functional interchangeability of Inv/Mxi-Spa T3SS proteins acting directly at the host-pathogen interface.
The loss of effective antimicrobials is reducing our ability to protect the global population from infectious disease. However, the field of antibiotic drug discovery and the public health monitoring of antimicrobial resistance (AMR) is beginning to exploit the power of genome and metagenome sequencing. The creation of novel AMR bioinformatics tools and databases and their continued development will advance our understanding of the molecular mechanisms and threat severity of antibiotic resistance, while simultaneously improving our ability to accurately predict and screen for antibiotic resistance genes within environmental, agricultural, and clinical settings. To do so, efforts must be focused toward exploiting the advancements of genome sequencing and information technology. Currently, AMR bioinformatics software and databases reflect different scopes and functions, each with its own strengths and weaknesses. A review of the available tools reveals common approaches and reference data but also reveals gaps in our curated data, models, algorithms, and data-sharing tools that must be addressed to conquer the limitations and areas of unmet need within the AMR research field before DNA sequencing can be fully exploited for AMR surveillance and improved clinical outcomes.
3rd year Biochemistry & Biomedical Sciences student Tammy Lau has joined us for her Biochem 3A03 (Biochemical Research Practice) course. Tammy will be collaborating with Dr. Lesley MacNeil in development of a bioinformatics pipeline for a new technology for tissue-specific expression profiling in the important model organism C. elegans. Support from this project comes from a new Michael G. DeGroote Institute for Infectious Disease Research (McMaster) Research Grant. Welcome Tammy!
Jia B, Raphenya AR, Alcock B, Waglechner N, Guo P, Tsang KK, Lago BA, Dave BM, Pereira S, Sharma AN, Doshi S, Courtot M, Lo R, Williams LE, Frye JG, Elsayegh T, Sardar D, Westman EL, Pawlowski AC, Johnson TA, Brinkman FS, Wright GD, & McArthur AG.
The Comprehensive Antibiotic Resistance Database (CARD; http://arpcard.mcmaster.ca) is a manually curated resource containing high quality reference data on the molecular basis of antimicrobial resistance (AMR), with an emphasis on the genes, proteins and mutations involved in AMR. CARD is ontologically structured, model centric, and spans the breadth of AMR drug classes and resistance mechanisms, including intrinsic, mutation-driven and acquired resistance. It is built upon the Antibiotic Resistance Ontology (ARO), a custom built, interconnected and hierarchical controlled vocabulary allowing advanced data sharing and organization. Its design allows the development of novel genome analysis tools, such as the Resistance Gene Identifier (RGI) for resistome prediction from raw genome sequence. Recent improvements include extensive curation of additional reference sequences and mutations, development of a unique Model Ontology and accompanying AMR detection models to power sequence analysis, new visualization tools, and expansion of the RGI for detection of emergent AMR threats. CARD curation is updated monthly based on an interplay of manual literature curation, computational text mining, and genome analysis.
This month we say farewell to Briony Lago as she returns to her undergraduate studies in Chemical Biology at McMaster. Briony joined us as part of her Chemical Biology Co-Op program and worked on both human muscle atrophy and zebrafish toxicology transcriptome studies, as well a curation of the Comprehensive Antibiotic Resistance Database. Her publications are below, with more on the way. Briony was also awarded a 2016 IIDR Summer Student Fellowship for her work. Good luck Briony!
- Jia, B., A.R. Raphenya, B. Alcock, N. Waglechner, P. Guo, K.K. Tsang, B.A. Lago, B.M. Dave, S. Pereira, A.N. Sharma, S. Doshi, M. Courtot, R. Lo, L.E. Williams, J.G. Frye, T. Elsayegh, D. Sardar, E.L. Westman, A.C. Pawlowski, T.A. Johnson, F.S.L. Brinkman, G.D. Wright, & A.G. McArthur. 2017. CARD 2017: expansion and model-centric curation of the Comprehensive Antibiotic Resistance Database. Nucleic Acids Research, 45, D566-573.
- Williams, L.M, B.A. Lago, A.G. McArthur, A.R. Raphenya, N. Pray, N. Saleem, S. Salas, K. Paulson, R.S. Mangar, Y. Liu, A.H. Vo, & J.A. Shavit. 2016. The transcription factor, Nuclear factor, erythroid 2 (Nfe2), is a regulator of the oxidative stress response during Danio rerio development. Aquatic Toxicology, 180, 141-154.
Antibiotic resistance is ancient and widespread in environmental bacteria. These are therefore reservoirs of resistance elements and reflective of the natural history of antibiotics and resistance. In a previous study, we discovered that multi-drug resistance is common in bacteria isolated from Lechuguilla Cave, an underground ecosystem that has been isolated from the surface for over 4 Myr. Here we use whole-genome sequencing, functional genomics and biochemical assays to reveal the intrinsic resistome of Paenibacillus sp. LC231, a cave bacterial isolate that is resistant to most clinically used antibiotics. We systematically link resistance phenotype to genotype and in doing so, identify 18 chromosomal resistance elements, including five determinants without characterized homologues and three mechanisms not previously shown to be involved in antibiotic resistance. A resistome comparison across related surface Paenibacillus affirms the conservation of resistance over millions of years and establishes the longevity of these genes in this genus.
See more: McMaster Daily News
The McArthur lab and the Comprehensive Antibiotic Resistance Database are proud to have contributed to the Genome Canada – Canadian Food Inspection Agency Forum on Genomics and Antimicrobial Resistance. The two-day event brought together over sixty leading experts from academic, government, industry and commodities groups to address the challenge of AMR and discuss a path forward. A summary of the Forum and the Workshop Report are now online.