A5010537293- Antifungal resistance and susceptibility
- Fungal Infections and Studies
- Bacteriophages and microbial interactions
- Bacterial Genetics and Biotechnology
- Carbohydrate Chemistry and Synthesis
- Peptidase Inhibition and Analysis
- Escherichia coli research studies
- Healthcare cost, quality, practices
- Glycosylation and Glycoproteins Research
- Pneumocystis jirovecii pneumonia detection and treatment
- Legume Nitrogen Fixing Symbiosis
- Genomics and Phylogenetic Studies
- Monoclonal and Polyclonal Antibodies Research
- Fungal and yeast genetics research
- Salmonella and Campylobacter epidemiology
- Bacillus and Francisella bacterial research
- Plant-Microbe Interactions and Immunity
- Health Systems, Economic Evaluations, Quality of Life
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Antibiotic Resistance in Bacteria
- Plant Pathogenic Bacteria Studies
- Helminth infection and control
- Trypanosoma species research and implications
- Fungal Biology and Applications
- Healthcare Policy and Management
University of Toronto
2019-2023
University of Guelph
2014-2022
Fungal pathogens pose a global threat to human health, with Candida albicans among the leading killers. Systematic analysis of essential genes provides powerful strategy discover potential antifungal targets. Here, we build machine learning model generate genome-wide gene essentiality predictions for C. and expand largest functional genomics resource in this pathogen (the GRACE collection) by 866 genes. Using chemogenomic analyses, define function three uncharacterized roles kinetochore...
Hsp90 is a conserved molecular chaperone that assists in the folding and function of diverse cellular regulators, with profound impact on biology, disease, evolution. As central hub protein interaction networks, engages hundreds protein–protein interactions within eukaryotic cells. These include client proteins, which physically interact depend for stability or function, as well co-chaperones partner proteins modulate function. Currently, there are no methods to accurately predict...
Significance Polysaccharide capsules are protective surface layers that enhance virulence of many pathogenic bacteria. Salmonella enterica serovar Typhi is the causative agent typhoid fever, and it produces capsular polysaccharide known as “Vi antigen.” This glycan part some current vaccines. In Gram-negative bacteria, polysaccharides attached to a conserved glycolipid anchors cell required for its transport across envelope. S . follows different strategy; this work identifies reducing...
Manogepix is a broad-spectrum antifungal agent that inhibits glycosylphosphatidylinositol (GPI) anchor biosynthesis. Using whole-genome sequencing, we characterized two efflux-mediated mechanisms in the fungal pathogens Candida albicans and parapsilosis resulted decreased manogepix susceptibility. In C. , gain-of-function mutation transcription factor gene ZCF29 activated expression of ATP-binding cassette transporter genes CDR11 SNQ2 .
Abstract Metabolic flexibility enables fungi to invade challenging host environments. In Candida albicans , a common cause of life-threatening infections in humans, an important contributor is alternative oxidase (Aox) activity. Dramatic induction this activity occurs under respiratory-stress conditions, which impair the classical electron transport chain (ETC). Here, we show that deletion inducible AOX2 gene cripples C. virulence mice by increasing immune recognition. To investigate...
Significance Capsules are critical virulence determinants for bacterial pathogens. They composed of capsular polysaccharides (CPSs) with diverse structures, whose assembly on the cell surface is often powered by a conserved ABC transporter. Current capsule-assembly models include contiguous trans-envelope channel directing nascent CPSs from transporter to surface. This apparatus an attractive target antivirulence antimicrobial development. work describes CPS depolymerizing lyase enzyme found...
is a leading human fungal pathogen that often causes life-threatening infections in immunocompromised individuals. The ability of
Candida albicans is a leading cause of death due to systemic fungal infections. Poor patient outcomes are attributable the limited number antifungal classes and increasing prevalence drug resistance. Protein kinases have emerged as rewarding targets in development drugs for diverse diseases, yet remain untapped quest new antifungals. Here, we performed comprehensive analysis C. kinome identify genes which loss-of-function confers hypersensitivity two most widely deployed antifungals,...
The glycosylphosphatidylinositol anchor biosynthesis inhibitor gepinacin demonstrates broad-spectrum antifungal activity and negligible mammalian toxicity in culture but is metabolically labile. stability bioactivity of 39 analogs were tested vitro to identify LCUT-8, a stabilized lead with increased potency promising single-dose pharmacokinetics. Unfortunately, no was seen at the maximum dosing achievable neutropenic rabbit model. Nevertheless, structure-activity relationships identified...
Invasive fungal infections have mortality rates of 30–90%, depending on patient co-morbidities and the causative pathogen. The frequent emergence drug resistance reduces efficacy currently approved treatment options, highlighting an urgent need for antifungals with new modes action. Addressing this need, fosmanogepix (N-phosphonooxymethylene prodrug manogepix; MGX) is first in a class gepix drugs, acts as broad-spectrum, orally bioavailable inhibitor essential glycosylphosphatidylinositol...
In the human fungal pathogen Candida albicans , ARO1 encodes an essential multi-enzyme that catalyses consecutive steps in shikimate pathway for biosynthesis of chorismate, a precursor to folate and aromatic amino acids. We obtained first molecular image C. Aro1 reveals architecture all five enzymatic domains their arrangement context full-length protein. forms flexible dimer allowing relative autonomy function individual domains. Our activity cellulo data suggest only four Aro1’s are...
Vi antigen is an extracellular polysaccharide produced by Salmonella enterica Typhi, Citrobacter freundii, and some soil bacteria belonging to the Burkholderiales. In Vi-antigen capsule protects bacterium against host defenses, glycan used in a current glycoconjugate vaccine protect typhoid. glycolipid assembled cytoplasm translocated cell surface export complex driven ABC transporter. efficient cell-surface retention of layer depend on reducing terminal acylated-HexNAc moiety. Although...