Working at the intersection, of biology, chemistry, and computation, I combine large-scale genomics with chemical biology and chemical genetics to systematically discover new therapeutics.
Currently, I'm focussed on finding new treatments for tuberculosis (TB), a disease that kills 1.5 million people per year. Drug resistance is rising steadily, partly fueled by the standard of care for drug-susceptible TB: a poorly-tolerated regimen of ethambutol, isoniazid, pyrazinamide, and rifampin.
The causative agent of TB, Mycobacterium tuberculosis, has co-evolved with the human immune system to be an expert pathogen. It tolerates treatment by conventional antibiotics like the beta-lactams (think penicillin).
My work aims to find drugs which kill M. tuberculosis in new ways. By inhibiting new intracellular targets, current resistance can be circumvented, but this is a difficult task. With my colleagues at the Broad Institute, University of Massachusetts Medical School, Weill Cornell Medical College, and Harvard T.H. Chan School of Public Health, I developed a method to quickly prioritize potential new TB drugs based on their targets.
In the future, I plan to use my systems chemical biology approach to discover new drug combinations that could subvert the antimicrobial resistance crisis by driving pathogens into an evolutionary dead-end, and find antimicrobials that focus on saving the patient rather than directly killing the bug.
Large-scale chemical-genetic strategy to design antimicrobial combination chemotherapy for Mycobacterium tuberculosis
ACS Infectious Diseases, Jan 2020, 6(1), 56–63
A point of inflection and reflection on systems chemical biology
ACS Chemical Biology, Dec 2019, 14(12), 2497–2511
Large-scale chemical-genetics yields new M. tuberculosis inhibitor classes
Nature, Jul 2019, 571, 72-78
A structural model of a P450-ferredoxin complex from orientation-selective double electron-electron resonance spectroscopy
Journal of the American Chemical Society, Feb 2018, 140(7), 2514-2527
Partial fusion of a cytochrome P450 system by carboxy-terminal attachment of putidaredoxin reductase to P450cam (CYP101A1)
Catalysis Science and Technology, Sep 2016, 6(20), 7549-7560
Tailoring an alien ferredoxin to support native-like P450 monooxygenase activity
Chemical Communications, Dec 2012, 48(95), 11692-11694
Structural and functional characterization of Rpn12 identifies residues required for Rpn10 proteasome incorporation
Biochemical Journal, Nov 2012, 448(1), 55-65
The crystal structures of 4-methoxybenzoate bound CYP199A2 and CYP199A4: structural changes on substrate binding and the identification of an anion binding site
Dalton Transactions, Jul 2012, 41(28), 8703-8714
Selective oxidative demethylation of veratric acid to vanillic acid by CYP199A4 from Rhodopseudomonas palustris HaA2
Molecular BioSystems, Jan 2010, 6(1), 206-214
Protein recognition in ferredoxin-P450 electron transfer in the class I CYP199A2 system from Rhodopseudomonas palustris
Journal of Biological Inorganic Chemistry, Mar 2010, 15(3), 315-28
Crystal structure of a ferredoxin reductase for the CYP199A2 system from Rhodopseudomonas palustris
Proteins, Dec 2009, 77(4), 867-880