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New biarsenical ligands and tetracysteine motifs for protein labeling in vitro and in vivo: synthesis and biological applications.
Affinities in vitro and detection limits in living cells are optimized with Xaa-Xaa = Pro-Gly, suggesting that the preferred peptide conformation is a hairpin rather than the previously proposed alpha-helix.
Kinetics of Avibactam Inhibition against Class A, C, and D β-Lactamases
Kinetic parameters of inhibition as well as acyl enzyme stability are reported against six clinically relevant enzymes, providing the foundation for future structural and mechanistic enzymology experiments.
Fluorescent sensors for Zn(2+) based on a fluorescein platform: synthesis, properties and intracellular distribution.
The X-ray crystal structure of a 2:1 Zn(2+):Zinpyr-1 complex has been solved, and is the first structurally characterized example of a complex of fluorescein substituted with metal binding ligands, making them well-suited for intracellular applications.
Avibactam is a covalent, reversible, non–β-lactam β-lactamase inhibitor
It is shown that avibactam is a covalent, slowly reversible inhibitor, which is a unique mechanism of inhibition among β-lactamase inhibitors.
Selection and molecular characterization of ceftazidime/avibactam-resistant mutants in Pseudomonas aeruginosa strains containing derepressed AmpC.
The development of high-level resistance to ceftazidime/avibactsam appears to occur at low frequency, but structural modifications in AmpC can occur that impact the ability of avibactam to inhibit the enzyme and thereby protect ceftzidime from hydrolysis.
ESKAPEing the labyrinth of antibacterial discovery
Findings from target-based and phenotypic screening efforts carried out at AstraZeneca over the past decade are described, some of the subsequent chemistry challenges are discussed and a description of new approaches comprising a combination of computational modelling and advanced biological tools which may pave the way towards the discovery of new antibacterial agents are described.
Evaluation of pKa Estimation Methods on 211 Druglike Compounds
The pK(a) values of 211 discovery (druglike) compounds were determined experimentally using capillary electrophoresis coupled with ultraviolet spectroscopy and a novel fitting algorithm, and the accuracy of those two methods and Marvin was statistically indistinguishable, with a root-mean-squared error of about 1 pK (a) unit compared to experiment.
A New Cell-Permeable Fluorescent Probe for Zn2+
Although Zn2+ is abundant in eukaryotes and most is tightly bound, pools of chelatable Zn 2+ have been imaged in living cells with concentrations ranging from sub-nM in undifferentiated mammalian
Novel Bacterial NAD+-Dependent DNA Ligase Inhibitors with Broad-Spectrum Activity and Antibacterial Efficacy In Vivo
A novel class of substituted adenosine analogs was discovered by target-based high-throughput screening (HTS), and these compounds were optimized to render them more effective and selective inhibitors of LigA, validating LgA as a target for antibacterial therapy.
Design and Evaluation of a Peptidyl Fluorescent Chemosensor for Divalent Zinc
The design, synthesis, and evaluation of a selective fluorescent chemosensor, sensitive to nanomolar concentrations of Zn^(2+), using a polypeptide architecture as the framework for metal ion recognition.