Mtb-Biotin

We have a well-established collaboration with the Aldrich laboratory in UMN Medicinal Chemistry to help characterize and develop inhibitors of enzymes of biotin or biotin-dependent biosynthesis essential for the infectious proliferation of mycobacterium tuberculosis in the human host. Our work has been funded by a grant from the NIH NIAID (R01 AI091790-01) awarded to Principal Investigator Dirk Schnappinger of Cornell University, a leading Mtb microbiologist. Structural work has primarily centered on two enzymes: BioA, a PLP-dependent transaminase that catalyzes the second step in biotin biosynthesis, and BirA, a biotin-protein ligase essential for mycolic acid (cell wall) biosynthesis. Inhibitors are synthesized and enzymatically characterized in the Aldrich lab, we perform co-crystallization studies and biophysics, and the Cornell group performs in vitro evaluation in cells.

Initial approaches to inhibitor development focused on mechanism-based inhibitors of BioA [1,2,3] or transition state analogs of BirA[4]. BioA inhibitors have also been discovered by biophysical fragment screening conducted in our laboratory [5,6], and by screening of compound libraries for whole-cell activity [7]. Most recently, inhibitor optimization has been possible by combining structural information, and data describing the the thermodynamics of binding to create highly potent and selective inhibitors of Mtb growth selectively targeting biotin biosynthesis [8].

Publications

1. B.P. Duckworth, T.W.Geders, D. Tiwari, H.I.Boshoff, P.A.Sibbald, C.E.Barry, D.Schnappinger, B.C. Finzel, C.C. Aldrich. (2011) “Bisubstrate Adenylation Inhibitors of Biotin Protein Ligase from Mycobacterium tuberculosis”. Chem. & Biol., 18(11):1433-41. PMID:22118677. DOI: 10.1016/j.chembiol.2011.08.013. PDB entry 3rux.

2. Shi, C., Geders, T., Park, S.W., Wilson, D., Boshoff, H., Orisadipe, A., Barry, C., Schnappinger, D., Finzel, B., Aldrich, C. “Mechanism-Based Inactivation by Aromatization of the Transaminase BioA Involved in Biotin Biosynthesis in Mycobacterium tuberculosis.” (2011). J. Am. Chem. Soc., 133(45):18194-201. PMID:21988601. DOI: 10.1021/ja204036t. PDB entries 3tft, 3tfu

3. C. Eiden, K. M. Maize, B.C. Finzel, J.D. Lipscomb, C.C. Aldrich (2017) "Rational Optimization of Mechanism-Based Inhibitors Through Determination of the Microscopic Rate Constants of Inactivation". J. Amer. Chem. Soc. 139:7132-7135. PMID:28510452. DOI: 10.1021/jacs.7b00962. PDB entry 5te2.

4. M.R. Bockman, A.S. Kalinda, R. Petrelli, T. De la Mora-Rey, D. Tiwari, F. Liu, S. Dawadi, M. Nandakumar, K.Y. Rhee, D. Schnappinger, B.C. Finzel, C.C. Aldrich. (2015) “Targeting Mycobacterium tuberculosis Biotin Protein Ligase (MtBPL) with Nucleoside-Based Bisubstrate Adenylation Inhibitors” J. Med Chem. 58(18) 7349-7369. PMID:26299766. DOI: 10.1021/acs.jmedchem.5b00719. PDB entries 4xtu, 4xtv, 4xtw, 4xtx, 4xty, 4xtz, 4xu0, 4xu1, 4xu2, and 4xu3.

5. R. Dai, D. Wilson, T.W. Geders, C.C. Aldrich, B.C. Finzel. (2014) "Inhibition of Mycobacterium tuberculosis Transaminase BioA by Aryl Hydrazines and Hydrazides ". ChemBioChem. 15(4):575-586. PMID:24482078. DOI:10.1002/cbic.201300748. PDB entries 4cxq, 4cxr, 4mqp, 4mqq, 4mqr.

6. R. Dai, T.W. Geders, F. Liu, S.W. Park, D. Schnappinger, C.C. Aldrich, B.C. Finzel. (2015) "Fragment-based Exploration of Binding Site Flexibility in Mycobacterium tuberculosis BioA". J. Med. Chem. 58:5208-5217. PMID:26068403. DOI:10.1021/acs.jmedchem.5b00092. PDB entries 4wya, 4wyc, 4wyd, 4wye, 4wyf, 4wyg and 4xew.

7. S.W. Park, D. Casalena, D. Wilson, R. Dai, P. Nag, J.P. Boyce, J. Bittker, S. Schreiber, B.C. Finzel, D. Schnappinger, C.C. Aldrich. (2015) "Target-Based Identification of Whole-Cell Active Inhibitors of Biotin Biosynthesis in Mycobacterium tuberculosis". Chem. Biol. 22(1):76-87. PMID: 25556942. DOI: 10.1016/j.chembiol.2014.11.012. PDB entries 4w1v, 4w1w and 4w1x.

8. F. Liu, S. Dawadi, K. M. Maize, R. Dai, S.W. Park, D. Schnappinger, B.C. Finzel, C.C. Aldrich (2017) "Structure-Based Optimization of Pyridoxal 5′-Phosphate (PLP)-Dependent Transaminase Enzyme (BioA) Inhibitors that Target Biotin Biosynthesis in Mycobacterium tuberculosis". J. Med. Chem. 60(13):5507-5520. PMID:28594172. DOI:10.1021/acs.jmedchem.7b00189. PDB entries 4xjp, 4xjo, 5kgs, 5kgt.