A5062107413- Bacterial Genetics and Biotechnology
- Gut microbiota and health
- Genomics and Phylogenetic Studies
- Microbial Metabolic Engineering and Bioproduction
- Bacterial biofilms and quorum sensing
- DNA Repair Mechanisms
- Biochemical and Structural Characterization
- Microbial Natural Products and Biosynthesis
- Monoclonal and Polyclonal Antibodies Research
- Bacteriophages and microbial interactions
- Escherichia coli research studies
- CRISPR and Genetic Engineering
- Vitamin C and Antioxidants Research
- Probiotics and Fermented Foods
- bioluminescence and chemiluminescence research
- Marine Bivalve and Aquaculture Studies
- Cellular transport and secretion
- Advancements in Transdermal Drug Delivery
- Cancer Research and Treatments
- Gastrointestinal motility and disorders
- Carcinogens and Genotoxicity Assessment
- Enzyme Catalysis and Immobilization
- Digital Imaging for Blood Diseases
- Transgenic Plants and Applications
- Receptor Mechanisms and Signaling
Princeton University
2021-2025
Yale University
2015-2021
University of Pittsburgh
2012
Colibactin is a complex secondary metabolite produced by some genotoxic gut Escherichia coli strains. The presence of colibactin-producing bacteria correlates with the frequency and severity colorectal cancer in humans. However, because colibactin has not been isolated or structurally characterized, studying physiological effects human difficult. We used combination genetics, isotope labeling, tandem mass spectrometry, chemical synthesis to deduce structure colibactin. Our structural...
Escherichia coli is a common inhabitant of the human microbiota and beacon model organism in biology. However, an understanding its signaling systems that regulate population-level phenotypes known as quorum sensing remain incomplete. Here, we define structure biosynthesis autoinducer-3 (AI-3), metabolite previously unknown involved pathogenesis enterohemorrhagic E. (EHEC). We demonstrate novel AI-3 analogs are derived from threonine dehydrogenase (Tdh) products "abortive" tRNA synthetase...
Attachment is a necessary first step in bacterial commitment to surface-associated behaviors that include colonization, biofilm formation, and host-directed virulence. The Gram-negative opportunistic pathogen Pseudomonas aeruginosa can initially attach surfaces via its single polar flagellum. Although many bacteria quickly detach, some become irreversibly attached express structures, such as Type IV pili, behaviors, including twitching motility initiation. P. lack the GTPase FlhF assemble...
Certain commensal Escherichia coli contain the clb biosynthetic gene cluster that codes for small molecule prodrugs known as precolibactins. Precolibactins are converted to colibactins by N-deacylation; latter postulated be genotoxic and contribute colorectal cancer formation. Though advances toward elucidating (pre)colibactin biosynthesis have been made, functions mechanisms of several products remain poorly understood. Here we report 2.1 Å X-ray structure molecular function ClbS, a product...
Modular polyketide synthases (PKSs) and nonribosomal peptide synthetases (NRPSs) comprise giant multidomain enzymes responsible for the "assembly line" biosynthesis of many genetically encoded small molecules. Site-directed mutagenesis, protein biochemical, structural studies have focused on elucidating catalytic mechanisms individual proteins domains within these megasynthases. However, probing their functions at cellular level typically has invoked complete deletion (or overexpression)...
Pseudomonas aeruginosa is a leading cause of hospital-acquired infections and it resistant to many current antibiotic therapies, making development new anti-microbial treatments imperative. The cell-to-cell communication process called quorum sensing controls P. pathogenicity. Quorum relies on the production, release, group-wide detection extracellular signal molecules autoinducers. enables bacteria synchronize group behaviors. possesses multiple quorum-sensing systems that control...
Colibactins are genotoxic secondary metabolites whose biosynthesis is encoded in the clb gene cluster harbored by certain strains of gut commensal Escherichia coli. Using synthetic colibactin analogues, we previously provided evidence that colibactins alkylate DNA addition a nucleotide to an electrophilic cyclopropane intermediate. However, natural colibactin-nucleobase adducts have not been identified, best our knowledge. Here present first identification such adducts, derived from...
Colibactins are genotoxic secondary metabolites produced in select Enterobacteriaceae, which induce downstream DNA double-strand breaks (DSBs) human cell lines and thought to promote the formation of colorectal tumors. Although key structural functional features colibactins have been elucidated, full molecular mechanisms regulating these phenotypes remain unknown. Here, we demonstrate that free model DSBs cultures do not require delivery by host bacteria. Through domain-targeted editing, a...
Abstract Attachment is a necessary first step in bacterial commitment to surface-associated behaviors that include colonization, biofilm formation, and host-directed virulence. The Gram-negative opportunistic pathogen Pseudomonas aeruginosa can initially attach surfaces via its single polar flagellum. Although many bacteria quickly detach, some become irreversibly attached express structures, such as Type IV pili, behaviors, including twitching motility initiation. P. lack the GTPase FlhF...
Abstract Colibactin is a gut microbiome metabolite of unknown structure that has been implicated in colorectal cancer formation. Several studies now suggest the tumorgenicity colibactin derives from interstrand cross-linking host DNA. Here we use combination genetics, isotope labeling, tandem MS, and chemical synthesis to deduce colibactin. Our structural assignment accounts for all known biosynthetic data suggests roles final unaccounted enzymes gene cluster. DNA cross-link degradation...
Colibactin is a genotoxic hybrid polyketide-nonribosomal peptide that drives colorectal cancer initiation. While clinical data suggest colibactin genotoxicity in vivo largely caused by the major DNA-cross-linking metabolite, locus produces diverse collection of metabolites with mostly unknown biological activities. Here, we describe 10 new pathway (1-10) are dependent on its α-aminomalonyl-carrier protein. The most abundant metabolites, 1 and 2, were isolated structurally characterized...
Select strains of E. coli in our gut encode the “colibactin” pathway, a nonribosomal peptide synthetase-polyketide synthase hybrid pathway phenotypically linked to inflammatory bowel disease and colorectal cancer patients. A variety cell biology animal model studies have previously been reported for but responsible small molecules driving phenotypes remained enigmatic. Employing molecular networking tools, we developed “pathway-targeted” approach map colibactin from both meningitis pathogen...
Abstract Colibactins are genotoxic secondary metabolites produced in select Enterobacteriaceae, which induce downstream DNA double-strand breaks (DSBs) human cell lines and thought to promote the formation of colorectal tumors. Although key structural functional features colibactins have been elucidated, full molecular mechanisms regulating these phenotypes remain unknown. Here, we demonstrate that free model DSBs cultures do not require delivery by host bacteria. Through domain-targeted...