A5002464699- Antibiotic Resistance in Bacteria
- Bacterial biofilms and quorum sensing
- Antimicrobial Peptides and Activities
- Bacterial Genetics and Biotechnology
- Bacteriophages and microbial interactions
- Biochemical and Structural Characterization
- Microbial Natural Products and Biosynthesis
- Drug Transport and Resistance Mechanisms
- Pharmaceutical and Antibiotic Environmental Impacts
- Plant-based Medicinal Research
- Chemical Synthesis and Analysis
- Phenothiazines and Benzothiazines Synthesis and Activities
McMaster University
2019-2024
Center for Discovery
2023
Iron is essential for many biological functions in bacteria, but its poor solubility a limiting factor growth. Bacteria produce siderophores, soluble natural products that bind iron with high affinity, to overcome this challenge. Siderophore-iron complexes return the cell through specific outer membrane transporters. The opportunistic pathogen Pseudomonas aeruginosa makes multiple transporters recognize own pyoverdine and pyochelin, xenosiderophores produced by other bacteria or fungi, which...
Pseudomonas aeruginosa is a biofilm-forming opportunistic pathogen and intrinsically resistant to many antibiotics. In high-throughput screen for molecules that modulate biofilm formation, we discovered the thiopeptide antibiotic thiostrepton (TS), which considered be inactive against Gram-negative bacteria, stimulated P. formation in dose-dependent manner. This phenotype characteristic of exposure antimicrobial compounds at subinhibitory concentrations, suggesting TS was active Supporting...
The outer membrane of gram-negative bacteria prevents many antibiotics from reaching intracellular targets. However, some antimicrobials can take advantage iron import transporters to cross this barrier. We showed previously that the thiopeptide antibiotic thiocillin exploits nocardamine xenosiderophore transporter, FoxA, opportunistic pathogen Pseudomonas aeruginosa for uptake. Here, we show FoxA also transports bisucaberin and describe at 2.5 Å resolution crystal structure bound FoxA....
Thiopeptides are a class of antibiotics that active against Gram-positive bacteria and inhibit translation. They were considered inactive Gram-negative due to their inability cross the outer membrane. However, we discovered previously member this class, thiostrepton (TS), has activity Pseudomonas aeruginosa Acinetobacter baumannii under iron-limiting conditions. TS hijacks pyoverdine siderophore receptors P. membrane synergizes with iron chelators.To test other thiopeptides for antimicrobial...
Traditional antibacterial screens rely on growing bacteria in nutrient-replete conditions which are not representative of the natural environment or sites infection. Instead, screening more physiologically relevant may reveal novel activity for existing antibiotics. Here, we screened a panel antibiotics reported to lack against opportunistic Gram-negative bacterium, Pseudomonas aeruginosa, under low-nutrient and low-iron conditions, discovered that glycopeptide vancomycin inhibited growth P....
Pseudomonas aeruginosa is a multidrug-resistant nosocomial pathogen. We showed previously that thiostrepton (TS), Gram-positive thiopeptide antibiotic, imported via pyoverdine receptors and synergizes with iron chelator deferasirox (DSX) to inhibit the growth of P. Acinetobacter baumannii clinical isolates. A small number A. isolates were resistant combination, prompting us search for other compounds could synergize TS against those strains.
ABSTRACT Iron is essential for many biological functions in bacteria but its poor solubility a limiting factor growth. Bacteria produce siderophores, soluble natural products that bind iron with high affinity, to overcome this challenge. Siderophore-iron complexes return the cell through specific outer-membrane transporters. The opportunistic pathogen Pseudomonas aeruginosa makes multiple transporters recognize own pyoverdine and pyochelin, xenosiderophores produced by other bacteria, which...
To cause infection, bacterial pathogens must overcome host immune factors and barriers to nutrient acquisition. Reproducing these aspects of physiology in vitro has shown great promise for antibacterial drug discovery. When used as a growth medium, human serum replicates several the environment, including innate immunity iron limitation. We previously reported that high-throughput chemical screen using medium enabled discovery novel inhibitors overlooked by conventional screens. Here, we...
ABSTRACT Pseudomonas aeruginosa is a biofilm-forming opportunistic pathogen and intrinsically resistant to many antibiotics. In high-throughput screen for molecules that modulate biofilm formation, we discovered the thiopeptide antibiotic, thiostrepton (TS) - considered inactive against Gram-negative bacteria stimulated P. formation in dose-dependent manner. This phenotype characteristic of exposure antimicrobial compounds at sub-inhibitory concentrations, suggesting TS was active ....
ABSTRACT Thiopeptides are a class of Gram-positive antibiotics that inhibit protein synthesis. They have been underutilized as therapeutics due to solubility issues, poor bioavailability, and lack activity against Gram-negative pathogens. We discovered recently member this family, thiostrepton, has Pseudomonas aeruginosa Acinetobacter baumannii under iron-limiting conditions. Thiostrepton uses pyoverdine siderophore receptors cross the outer membrane, combining thiostrepton with an iron...
Abstract Traditional antibacterial screens rely on growing bacteria in nutrient-replete conditions which are not representative of the natural environment or sites infection. Instead, screening more physiologically relevant may reveal novel activity for existing antibiotics. Here, we screened a panel antibiotics reported to lack against opportunistic Gram-negative bacterium, Pseudomonas aeruginosa, under low-nutrient conditions, and discovered that glycopeptide vancomycin inhibited growth P....
ABSTRACT Pseudomonas aeruginosa is a multidrug-resistant nosocomial pathogen. We showed previously that thiostrepton (TS), gram-positive thiopeptide antibiotic, was imported via pyoverdine receptors and synergized with iron chelator deferasirox (DSX) to inhibit the growth of P. Acinetobacter baumannii clinical isolates. A small number A. isolates were resistant combination, prompting us search for other compounds could synergize TS against those strains. From literature surveys we selected...
Abstract The outer membrane of Gram-negative bacteria prevents many antibiotics from reaching intracellular targets. However, some antimicrobials can take advantage iron import transporters to cross this barrier. We showed previously that the thiopeptide antibiotic, thiocillin, exploits nocardamine (ferrioxamine E) xenosiderophore transporter, FoxA, opportunistic pathogen Pseudomonas aeruginosa for uptake. Here we show FoxA also transports bisucaberin and describe at 2.5 Å resolution first...