Peter J. Tonge
Professor
B.Sc., 1982, University of Birmingham, England
Ph.D., 1986, University of Birmingham, England
SERC-NATO Postdoctoral Research Fellowship,
National Research Council Canada, 1986-1988;
Alfred P. Sloan Research Fellowship, 2001.

Director of Tuberculosis Research, Insitute for Chemical Biology and Drug Discovery

Member of the Graduate Programs in Biophysics, Biochemistry and Structural Biology, Molecular and Cellular Biology, Molecular Genetics and Microbiology, Molecular and Cellular Pharmacology

Tel: (631) 632-7907
Fax: (631) 632 7960
Email: peter.tonge@sunysb.edu
Publications

Tonge Group Web Page

Recent News: Funding for Tuberculosis Program

Research Summary

Microbial Enzyme Drug Targets

        An area of research that has grown out an interest in enzyme mechanisms involves our efforts to develop inhibitors of known or putative drug targets.  These studies are focused on pathogens such as Mycobacterium tuberculosis (MTB), Francisella tularensis and S. aureus and include enzymes from pathways involved in bacterial fatty acid biosynthesis as well as the biosynthesis of the electron carrier menaquinone.

Fatty Acid Biosynthesis

 
       Bacterial fatty acid biosynthesis is a validated target for drug discovery and our primary focus is on the enoyl reductase enzyme from this pathway (FabI).  We hypothesize that high affinity inhibition of the FabI enzyme class is coupled to ordering of a loop of amino acids close to the active site slow onset inhibitors bind to the enzyme.  Using structure-based approaches we developed a series of diphenyl ether inhibitors of InhA, the FabI enzyme from MTB.  The most potent first generation compound has a Ki value of 1 nM for InhA and MIC90 values of 1-2 μg/mL against sensitive and INH resistant strains of MTB (Sullivan et al. (2006) ACS. Chem. Biol. 1, 43-53).  Select compounds in this series are also nM inhibitors of the homologous enzymes from Francisella tularensis and Staphylococcus aureus, with MIC90 values as low as 0.05 μg/mL.

Future Directions:   The nanomolar InhA inhibitors have activity against drug resistant TB but are poorly bioavailable.  We are now expanding the chemical diversity of our compound libraries to improve the ADME properties of the inhibitors.  This project requires close collaboration between compound design and synthesis, and studies involving pharmacokinetics, pharmacodynamics and compound evaluation in animal models of TB infection.  In addition, we are focusing our efforts to probe interactions within the cell that are critical for enzyme and inhibitor activity.  This will involve mass spectrometry and the dissection of protein-protein interactions using chemical tools.  We are also expanding our inhibitor discovery efforts to other enzymes and we plan to screen focused chemical libraries using transferred NOE NMR spectroscopy to obtain inter-ligand NOEs .

Menaquinone Biosynthesis

        Menaquinone (MK) is the sole quinone in the mycobacterial electron transport chain.  Enzymes involved in MK biosynthesis are promising drug targets since the pathway is absent in humans and also because compounds that affect respiration may be active against latent MTB populations.  We have initiated a coordinated series of activities to investigate the importance of this pathway including cloning, expressing and characterizing the putative TB men enzymes, as well as studying MK biosynthesis using mass spectrometry to follow the incorporation of isotopically labeled precursors into MK.  We have concentrated our efforts on the enzymes that convert O-succinylbenzoic acid to dihydroxynapthoate (MenE and MenB) as well as MenF, the isochorismate synthase that initiates MK biosynthesis.  So far we have been unable to identify the MenF homolog in MTB.  However MbtI, the salicylate synthase required for mycobactin biosynthesis will also synthesize isochorismate under certain conditions suggesting that MbtI may also play a role in MK biosynthesis (Zwahlen et al (2007) Biochemistry, 46, 954-64).  Current studies are focused on understanding the molecular basis that controls product distribution in MbtI. 

Light Activated Proteins

        Interests in utilizing spectroscopic methods to elucidate the precisedetails of enzyme catalyzed reactions have expanded in several directions.  The ability of enzymes to promote catalysis through noncovalent interactions has important parallels with the control of photophysical properties exerted by the green fluorescent protein on the embedded chromophore.  Since optical and structural events in GFP occur on a very fast time scale following light absorption, our steady state vibrational methods have been supplemented with ultrafast time resolved infrared spectroscopy (TRIR).  A highlight of this work was the use of TRIR to obtain direct proof that the excited state proton transfer (ESPT) reaction in GFP results in the protonation of a glutamate close to the chromophore (Stoner-Ma et al. (2005) J. Am. Chem. Soc., 127, 2864-5). 

        Time resolved studies on GFP are now being expanded to other light activated molecules including the BLUF (Blue Light Receptor Using FAD) protein AppA, an antirepressor from Rhodobacter sphaeroides.  Light absorption by the AppA flavin chromophore causes subtle changes in chromophore-protein interactions that result in dissociation of AppA from the transcriptional repressor PpsR and the subsequent down regulation of photosystem biosynthesis.  Using TRIR we are studying how formation of the FAD excitation causes structural changes to the protein matrix that are thought to include rotation of a glutamine side chain that is hydrogen bonded to the chromophore.