A5029379360- Tuberculosis Research and Epidemiology
- Mycobacterium research and diagnosis
- Pneumonia and Respiratory Infections
- Cancer therapeutics and mechanisms
- Antibiotic Resistance in Bacteria
- Phenothiazines and Benzothiazines Synthesis and Activities
- Antimicrobial Resistance in Staphylococcus
- Pneumocystis jirovecii pneumonia detection and treatment
- Biochemical and Molecular Research
- Antibiotics Pharmacokinetics and Efficacy
- Diagnosis and treatment of tuberculosis
- Immune cells in cancer
- Infectious Diseases and Tuberculosis
- RNA and protein synthesis mechanisms
- Actinomycetales infections and treatment
- Infectious Diseases and Mycology
- Synthesis and Catalytic Reactions
- Pharmacological Effects of Natural Compounds
- Bacterial Infections and Vaccines
- Acute Lymphoblastic Leukemia research
- Gut microbiota and health
- Quinazolinone synthesis and applications
- Cytomegalovirus and herpesvirus research
- Bacteriophages and microbial interactions
- Fungal Infections and Studies
McGill University Health Centre
2020-2024
Massachusetts General Hospital
2024
McGill University
2020-2024
University of Lethbridge
2024
Statens Serum Institut
2024
Pennsylvania State University
2024
École Polytechnique Fédérale de Lausanne
2016-2020
Centre hospitalier de l'Université Laval
2013-2015
Université Laval
2009-2011
Since the vast majority of species solely rely on innate immunity for host defense, it stands to reason that a critical evolutionary trait like immunological memory evolved in this primitive branch our immune system. There is ample evidence vaccines such as bacillus Calmette-Guérin (BCG) induce protective responses (trained immunity) against heterologous pathogens. Here we show while BCG vaccination significantly reduces morbidity and mortality influenza A virus (IAV), fails provide...
Leprosy is a chronic human disease caused by the yet-uncultured pathogen Mycobacterium leprae. Although readily curable with multidrug therapy (MDT), over 200,000 new cases are still reported annually. Here, we obtain M. leprae genome sequences from DNA extracted directly patients' skin biopsies using customized protocol. Comparative and phylogenetic analysis of 154 genomes 25 countries provides insight into evolution antimicrobial resistance, uncovering lineages phylogeographic trends, most...
VCC234718, a molecule with growth inhibitory activity against Mycobacterium tuberculosis (Mtb), was identified by phenotypic screening of 15344-compound library. Sequencing VCC234718-resistant mutant Y487C substitution in the inosine monophosphate dehydrogenase, GuaB2, which subsequently validated to be primary molecular target VCC234718 Mtb. inhibits Mtb GuaB2 Ki 100 nM and is uncompetitive respect IMP NAD+. This compound binds at NAD+ site, after has bound, makes direct interactions IMP;...
Linezolid is a member of novel class antibiotics, with resistance already being reported. We used whole-genome sequencing on three independent Streptococcus pneumoniae strains made resistant to linezolid in vitro step-by-step fashion. Analysis the genome assemblies revealed mutations 23S rRNA gene all mutants including, notably, G2576T, previously recognized mutation. Mutations an additional 31 genes were also found at least one sequenced genomes. concentrated new that two mutants. All...
New drugs are needed to control the current tuberculosis (TB) pandemic caused by infection with
Macozinone (MCZ) is a tuberculosis (TB) drug candidate that specifically targets the essential flavoenzyme DprE1, thereby blocking synthesis of cell wall precursor decaprenyl phosphoarabinose (DPA) and provoking lysis Mycobacterium . As part MCZ backup program, we exploited structure-guided design to produce new series sulfone-containing derivatives, 2-sulfonylpiperazin 8-nitro 6-trifluoromethyl 1,3-benzothiazin-4-one, or sPBTZ.
The efficacy of the standardized four-drug regimen (comprising isoniazid, rifampin, pyrazinamide, and ethambutol) for treatment tuberculosis (TB) is menaced by emergence multidrug-resistant (MDR) extensively drug-resistant (XDR) strains Mycobacterium . Intensive efforts have been made to develop new antibiotics or repurpose old drugs, several these are currently being evaluated in clinical trials their antitubercular activity.
Benzothiazinones (BTZs) are a class of compounds found to be extremely potent against both drug-susceptible and drug-resistant Mycobacterium tuberculosis strains. The potency BTZs is explained by their specificity for target decaprenylphosphoryl-d-ribose oxidase (DprE1), in particular covalent binding the activated form compound critical cysteine 387 residue enzyme. To probe role C387, we used promiscuous site-directed mutagenesis introduce other codons at this position into dprE1 M....
The emergence of multi-drug (MDR-TB) and extensively-drug resistant tuberculosis (XDR-TB) is a major threat to the global management (TB) worldwide. New chemical entities are need treat drug-resistant TB. In this study, mode action new, potent quinazoline derivatives was investigated against Mycobacterium (M. tb). Four 11626141, 11626142, 11626252 11726148 showed good activity (MIC ranging from 0.02-0.09 μg/mL) low toxicity (TD50 ≥ 5μg/mL) in vitro M. tb strain H37Rv HepG2 cells,...
New drugs with new mechanisms of action are urgently required to tackle the global tuberculosis epidemic. Following FDA-approval ATP synthase inhibitor bedaquiline (Sirturo®), energy metabolism has become subject intense focus as a novel pathway exploit for drug development. This enthusiasm stems from fact that oxidative phosphorylation (OxPhos) and maintenance transmembrane electrochemical gradient essential viability replicating non-replicating Mycobacterium (M. tb), etiological agent...
Mycobacterium abscessus is the most common rapidly growing non-tuberculous mycobacteria to cause pulmonary disease in patients with impaired lung function such as cystic fibrosis. M . displays high intrinsic resistance antibiotics and inducible macrolides like clarithromycin. As such, clinically resistant entire regimen of front-line tuberculosis drugs, treatment that do inhibit lab results cure rates 50% or less. Here, we identified epetraborole (EPT) from MMV pandemic response box an...
Tigecycline is a broad-spectrum antibiotic acting at the level of 30S ribosomal subunit to inhibit translation. While Streptococcus pneumoniae remains susceptible tigecycline, resistance beginning emerge in some species and mainly involves efflux or mutations ribosome constituents. We describe here characterization S. mutants selected for tigecycline. Molecular determinants tigecycline were studied through WGS two series made resistant vitro stepwise fashion by reconstructing using DNA...
The production of itaconate by macrophages was only discovered in 2011. An increasing number studies have since revealed essential biological functions for this small molecule, ranging from antimicrobial to immunomodulator. antibacterial role has however been questioned because the estimated concentration (low-millimolar) is lower than minimum inhibitory (MIC) reported several bacterial strains (low-to-mid-millimolar). We note that some these investigations tended ignore high acidity diacid...
ABSTRACT The broad-spectrum fluoroquinolone ciprofloxacin is a bactericidal antibiotic targeting DNA topoisomerase IV and gyrase encoded by the parC gyrA genes. Resistance to in Streptococcus pneumoniae mainly occurs through acquisition of mutations quinolone resistance-determining region (QRDR) ParC GyrA targets. A role low-level resistance has also been attributed efflux systems. To look into at genome-wide scale discover additional implicated resistance, we performed whole-genome...
ABSTRACT Oxidants were shown to contribute the lethality of bactericidal antibiotics in different bacterial species, including laboratory strain Streptococcus pneumoniae R6. Resistance penicillin among S. R6 mutants was further protect against induction oxidants upon exposure unrelated compounds. In work described here, we expanded on these results by studying accumulation reactive oxygen species context antibiotic sensitivity and resistance clinical isolates. R6, penicillin, ciprofloxacin,...
Abstract Objectives The objective of this study was to characterize chromosomal mutations associated with resistance tetracycline in Streptococcus pneumoniae. Methods Chronological appearance two S. pneumoniae R6 mutants (R6M1TC-5 and R6M2TC-4) selected for determined by next-generation sequencing. A role the identified confirmed reconstructing a WT background. RNA sequencing performed on R6M1TC-5 R6M2TC-4 relative expression genes reported according R6. Differentially expressed were...
ABSTRACT Antibiotic development and treatment focus on bacterial growth inhibition, often with limited success. Here, we introduce Antimicrobial Single-Cell Testing (ASCT), an advanced imaging strategy to assess killing in real-time. By tracking 140 million bacteria generating over 20,000 vitro time-kill curves, can predict Mycobacterium tuberculosis outcomes mice humans link strain-specific survival (drug tolerance) abscessus clinical responses. Using ASCT, reveal drug tolerance as a...
Linezolid is an oxazolidinone antibiotic that inhibits the initiation of translation. Although resistance to linezolid uncommon event, it has been reported in clinical isolates. The genome sequence Streptococcus pneumoniae linezolid-resistant mutants recently revealed mutations associated with resistance. A proteomic and transcriptomic screen now reveals a possible increase metabolism transport carbohydrates these S. mutants. Several glycolytic proteins were shown be overexpressed resistant...
ABSTRACT A handful of nucleoid-associated proteins (NAPs) regulate the vast majority genes in a bacterial cell. H-NS, h istone-like n ucleoid- s tructuring protein, is one these NAPs and protects Escherichia coli from foreign gene expression. Though lacking any sequence similarity with E. Rv3852 was annotated as H-NS ortholog Mycobacterium tuberculosis , it resembles human histone H1. The role thoroughly investigated by immunoblotting, subcellular localization, construction an unmarked...
Abstract Mycobacterium avium subsp. paratuberculosis ( MAP ) is the causative agent of paratuberculosis, a chronic gastrointestinal disease affecting ruminants. This remains widespread in part due to limitations available diagnostics and vaccines. A representative small animal model could act as valuable tool for studying its pathogenesis develop new methods control, but current models are lacking. Streptomycin pre-treatment can reduce colonization resistance has previously been shown...
Abstract Objective: To circumvent the need for rationing personal protective equipment (PPE), we explored whether germicidal ultraviolet light (GUV) could be used to inactivate human coronaviruses on PPE, enabling safe reuse. Design: We performed a laboratory study assess ability of 2 commercially available portable GUV devices common cold (HCoV-229E and HCoV-OC43) severe acute respiratory syndrome coronavirus virus (SARS-CoV-2), which causes disease 2019 (COVID-19), surface whole N95...
<title>Abstract</title> The Mycobacterium tuberculosis complex (MTBC) includes <italic>M. tuberculosis</italic> (<italic>M. tb</italic>), the cause of human tuberculosis, and animal pathogens, bovis</italic> orygis</italic>, causes in a broad range mammalian hosts, including humans. Since late 1800s, tb</italic> have shown distinct differences clinical presentation virulence following experimental infection. However, pathogenicity orygis</italic> has yet to be subject investigation. Despite...
ABSTRACT Mycobacterium tuberculosis (Mtb), the pathogen responsible for (TB), is leading cause of bacterial disease-related death worldwide. Current antibiotic regimens treatment TB remain dated and suffer from long times as well development drug resistance. As such, search novel chemical modalities that have selective or potent anti-Mtb properties remains an urgent priority, particularly against multidrug-resistant (MDR) Mtb strains. Herein, we design synthesize 35 b enzo[c] p henanthridine...