A5032060415- Bacterial Genetics and Biotechnology
- Antibiotic Resistance in Bacteria
- Drug Transport and Resistance Mechanisms
- RNA and protein synthesis mechanisms
- Genomics and Phylogenetic Studies
- Bacteriophages and microbial interactions
- Antimicrobial Peptides and Activities
- Bacterial biofilms and quorum sensing
- Cellular transport and secretion
- Lipid Membrane Structure and Behavior
- Trypanosoma species research and implications
- Metal-Catalyzed Oxygenation Mechanisms
- Archaeology and Historical Studies
- Plant-Microbe Interactions and Immunity
- Spectroscopy and Quantum Chemical Studies
- Glycosylation and Glycoproteins Research
- Metabolomics and Mass Spectrometry Studies
- Ancient Mediterranean Archaeology and History
- Tuberculosis Research and Epidemiology
- Mass Spectrometry Techniques and Applications
- Marine and environmental studies
- Photosynthetic Processes and Mechanisms
- Chemical Synthesis and Analysis
Broad Institute
2018-2024
Massachusetts General Hospital
2018-2024
University of Massachusetts Boston
2024
Harvard University
2018-2024
Akebia Therapeutics (United States)
2021
University of Toronto
2009-2014
Hospital for Sick Children
2009-2014
SickKids Foundation
2012
Genomics offered the promise of transforming antibiotic discovery by revealing many new essential genes as good targets, but results fell short promise. While numerous factors contributed to disappointing yield, one factor was that for a bacterial species were often defined based on single or limited number strains grown under in vitro laboratory conditions. In fact, essentiality gene can depend both genetic background and growth condition. We thus developed strategy more rigorously defining...
Pseudomonas aeruginosa is a major bacterial pathogen associated with rising prevalence of antibiotic resistance. We evaluated the resistance mechanisms P. against POL7080, species-specific, first-in-class in clinical trials that targets lipopolysaccharide transport protein LptD. isolated series POL7080-resistant strains mutations two-component sensor gene pmrB .
Bacterial cell membranes contain several protein pumps that resist the toxic effects of drugs by efficiently extruding them. One family these pumps, small multidrug resistance proteins (SMRs), consists about 110 residues need to oligomerize form a structural pathway for substrate extrusion. As such, SMR oligomerization sites should constitute viable targets efflux inhibition, disrupting protein-protein interactions between helical segments. To explore this proposition, we are using Hsmr, an...
SUMMARY The surge of antimicrobial resistance threatens efficacy current antibiotics, particularly against Pseudomonas aeruginosa , a highly resistant gram-negative pathogen. asymmetric outer membrane (OM) P. combined with its array efflux pumps provide barrier to xenobiotic accumulation, thus making antibiotic discovery challenging. We adapted PROSPECT 1 target-based, whole-cell screening strategy, discover small molecule probes that kill mutants depleted for essential proteins localized at...
Multidrug transporters such as the small multidrug resistance (SMR) family of bacterial integral membrane proteins are capable conferring clinically significant to a variety common therapeutics. As antiporter ∼100 amino acids, SMRs must self-assemble into homo-oligomeric structures for efflux drug molecules. Oligomerization centered at transmembrane helix four (TM4) has been implicated in SMR assembly, but full complement residues required mediate its self-interaction remains be...
BsSco is a member of the Sco protein family involved in assembly Cu(A) center within cytochrome c oxidase. forms complex with Cu(II) that has properties consistent dithiolate ligation. Stopped-flow UV-visible absorbance and fluorescence coupled multiwavelength analysis reveal biphasic binding kinetics between Cu(II). An initial species appears centered at 382 nm copper concentration-dependent rate (2.9 x 10(4) M(-1) s(-1)). The decays first-order (1.5 s(-1)) to equilibrium form maximum 352...
Drug-resistant bacteria use several families of membrane-embedded transporters to remove antibiotics from the cell. One such family is small multidrug resistance proteins (SMRs) that, because their relatively size (ca. 110 residues with four transmembrane [TM] helices), must form (at least) dimers efflux drugs. Here, we a Lys-tagged synthetic peptide exactly same sequence as TM4 full-length SMR Hsmr Halobacterium salinarum [TM4 sequence: AcA(Sar)(3)-VAGVVGLALIVAGVVVLNVAS-KKK (Sar =...
Bacteria evade the effects of cytotoxic compounds through efflux activity membrane-bound transporters such as small multidrug resistance (SMR) proteins. Consisting typically ca. 110 residues with four transmembrane (TM) α-helices, crystallographic studies have shown that TM helix 1 (TM1) 3 (TM3) each monomer create a substrate binding "pocket" within membrane bilayer, while TM4-TM4 interaction accounts for primary dimer formation. Previous work from our lab has characterized highly conserved...
Protein transmembrane (TM) segments participating in helix–helix packing commonly contain small residue patterns (termed GG4 or "small-xxx-small" motifs) at i and + 4 positions. Within many TM - such as the glycophorin A (GpA) sequence L75IxxGVxxGVxxT87- Gly79-xxx-Gly83 motif often occurs combination with large, usually β-branched aliphatic residues adjacent positions, typified here by Val80 Val84 residues. To explore importance of local character on GpA dimerization, we made systematic...
Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) is a universally employed technique that separates proteins on the basis of molecular weight (MW). However, membrane are known to size anomalously SDS-PAGE calibrated with conventional standards, an issue complicates interpretation protein identity, purity, degradation, and/or stoichiometry. Here we describe preparation novel polyleucine hydrophobic standards for reduce average deviation apparent MW from formula natural 7%...
Genomics offered the promise of transforming antibiotic discovery by revealing many new essential genes as good targets, but results fell short promise. It is becoming clear that a major limitation was for bacterial species were often defined based on single or limited number strains grown under in vitro laboratory conditions. In fact, essentiality gene can depend both genetic background and growth condition. We thus developed strategy more rigorously defining core genome studying pathogen...
Pseudomonas aeruginosa is a major bacterial pathogen for which there rising antibiotic resistance. We evaluated the resistance mechanisms of P. against POL7080, species-specific, first-in-class in phase 3 clinical trials targeting lipopolysaccharide transport protein LptD. found mutations two-component regulator pmrB . Genome-wide transcriptomics and confocal microscopy studies together suggest that POL7080 vulnerable to same described previously polymyxins, including colistin, involve lipid...