Countering Antibiotic Resistance Mechanisms
Summary: The rise of new antibiotic resistance mechanisms is a global clinical health threat. We are studying an unusual metal-dependent β-lactamase called NDM-1 that has spread world-wide since its discovery in 2008, that is now present in community-acquired infections, and that provides resistance against almost an entire class of antibiotics. We study how this catalyst works and how ligands interact with its metal center. There are currently no drugs that counter its activity, so in addition to learning the fundamental science behind this and related enzymes, our work also directly contributes to developing new therapeutics.
Clinical Variants of New Delhi Metallo-beta-Lactamase Are Evolving to Overcome Zinc Scarcity , 2017 ACS Infect Dis
Dipicolinic Acid Derivatives as Inhibitors of New Delhi Metallo-beta-Lactamase-1, 2017 J Med Chem
Blocking Interbacterial Signaling Pathways
Summary: Many Gram negative pathogens coordinate expression of virulence factors through interbacterial signaling pathways in a process known as “quorum-sensing.” We are studying enzymes that block quorum sensing by recognizing and degrading the chemical signals used for communication. Our study of these enzymes informs the basic science of dinuclear zinc sites in catalysis, provides biochemical tools for manipulating quorum-sensing systems, and explores the application of these enzymes and their variants as therapeutic proteins.
Substrate Trapping in the Siderophore Tailoring Enzyme PvdQ, 2017 ACS Chem Biol
Structure and Biochemical Characterization of AidC, a Quorum-Quenching Lactonase with Atypical Selectivity, 2015 Biochemistry
Regulation of Nitric Oxide Production Through Methylated Arginines
Summary: Nitric oxide production is dysregulated in a number of disease states including septic shock, idiopathic pulmonary fibrosis and some cancers including melanoma. We are studying a regulatory mechanism in which endogenous inhibitors of nitric oxide production are controlled by the activity of enzymes in the pentein superfamily, specifically the dimethylarginine dimethylaminohydrolases (DDAHs). We are studying the mechanism of these enzymes and developing novel and potent inhibitors as the first stage in developing new drugs. We are also interested in understanding the structure and reactivity of the entire pentein superfamily and how some of these enzymes catalyze a single hydrolytic reaction, some catalyze two sequential hydrolytic reactions, and others instead catalyze amidino-transfer reactions.
Developing an irreversible inhibitor of human DDAH-1, an enzyme upregulated in melanoma. 2014 ChemMedChem
Developing Novel Covalent Enzyme Inhibitors
Summary: Inhibitors that make covalent bonds with their target enzymes have many applications as tools in chemical biology, and also can have therapeutic applications. We are developing and studying covalent protein modifiers. Three examples for targets discussed above are 1) 2-chloroacetamidines as selective and potent inhibitors of DDAH, 2) n-alkylboronates as picomolar inhibitors of PvdQ, and 3) beta-lactam degradation products that covalently modify NDM-1. As a result of fragment-based high-throughput screening, we recently discovered that simple 2- and 4-halopyridines can serve as novel covalent modifiers that can selectively target select pairs of residues found in target proteins. We are studying their modification mechanisms, their targets, and their use in medicinal chemistry and chemical biology applications.
The Taxonomy of Covalent Inhibitors 2018 Biochemistry
Selective Covalent Protein Modification by 4-Halopyridines Through Catalysis 2017 ChemBioChem
On the mechanism of dimethylarginine dimethylaminohydrolase inactivation by 4-halopyridines. 2011 J Am Chem Soc