Description of Research Expertise:
The work in the lab is focused in three areas: elucidating the genetic and metabolic regulatory networks that allow tuberculosis to persist in the human host for years, determination of the molecular basis of serine protease inhibition and mathematical modeling of complex biomolecular systems.
Pathogenesis of dormancy in Mycobacterium tuberculosis.
It is widely believed that oxygen limitation, amino acid starvation and carbon source restriction are involved in establishing and maintaining Mycobacterium tuberculosis in a dormant state. Correspondingly, emergence from dormancy is related to a partial or complete amelioration of these conditions. We have identified and are studying three genetic and enzyme systems that comprise regulatory networks in Mtb that may be invovled in Mtb pathogenesis. These are: 1) ribonucleotide reductase systems that carry out the reduction of ribonucleotides to deoxyribonucleotides--the rate limiting enzymatic step in DNA synthesis, 2) the cytochrome system and, 3) the stringent response system that regulates the expression of a complex network of genes. This work is supported by the NIH.
A new area of investigation known as biomolecular computation where complex computational operations are carried out using biomolecules, in particular using DNA. We showed how macromolecules can be manipulated to carry out fundamental logical operations and can be wired together as reversible logic gates. We are currently collaborating with members of the School of Engineering on modeling complex biological behavior using a hybrid systems approach that combines continuous and stochastic modalities. This work is supported by the NSF and DARPA
Enzymology and cell biology of serine proteases and serine protease inhibitors.
Serine proteases and serine protease inhibitors (serpins) play critical roles in a wide variety of biological processes including inflammation, coagulation and growth and development. We have proposed a general model for the mechanism of inhibition of serine proteases by serine protease inhibitors based on site directed mutagenesis, atomic resolution crystal structures and NMR spectroscopic analyses. We are currently exploring the consequences and extensions of this model. This work is supported by the NIH.
Chuang YM, Dutta NK, Hung CF, Wu TC, Rubin H, Karakousis PC: The stringent response factors PPX1 and PPK2 play an important role in Mycobacterium tuberculosis metabolism, biofilm formation, and sensitivity to isoniazid in vivo Antimicrob Agents Chemother : pii: AAC.01139-16.,2016.
Chuang YM, Bandyopadhyay N, Rifat D, Rubin H, Bader JS, Karakousis PC.: Deficiency of the novel exopolyphosphatase Rv1026/PPX2 leads to metabolic downshift and altered cell wall permeability in Mycobacterium tuberculosis MBio 6 (2): e02428,2015.
Rubin H, Selwood T, Yano T, Weaver DG, Loughran M, Costanzo MJ, Scott RW, Wrobel JE, Freeman KB, Reitz AB: Acinetobacter baumannii OxPhos inhibitors as selective anti-infective agents Bioorganic & Medicinal Chemistry Letters : 378-383,2015.
Schurig-Briccio LA, Yano T, Rubin H, Gennis RB: Characterization of the type 2 NADH:menaquinone oxidoreductases from Staphylococcus aureus and the bactericidal action of phenothiazines Biochim Biophys Acta 1837 (7): 954-63,2014.
Yano, T, Rahimian, M, Aneja, KK, Schechter, NS, Rubin, H: Mycobacterium tuberculosis Type-II NADH-Menaquinone Oxidoreductase (NDH-2) catalyzes electron transfer through a two-site ping-pong mechanism and has two quinone-binding sites Biochemistry 53 (7): 1179-90,2014.
Katzianer DS, Yano T, Rubin H, Zhu J: A high-throughput small-molecule screen to identify a novel chemical inhibitor of Clostridium difficile Int J Antimicrob Agents : 2014.
Thayil SM, Morrison N, Schechter N, Rubin H, Karakousis PC: The Role of the Novel Exopolyphosphatase MT0516 in Mycobacterium tuberculosis Drug Tolerance and Persistence PLoS One : e28076,2011.
Yano, T., Kassovska-Bratinova, S., Teh, J-S., Winkler, J., Sullivan, K., Isaacs, A., Schechter, N.M., and Rubin, H: Reduction of clofazimine by mycobacterial type 2 NADH:Quinone oxidoreductase: A pathway for the generation of bactericidal levels of reactive oxygen species J Biol Chem : 2011.
Dawes SS, Qarner DF, Tsenova L, Timm J, McKinney JD, Kaplan G, Rubin H, Mizrahi V: Ribonucleotide reduction in Mycobacterium tuberculosis. Function and expression of the class Ib and class II ribonucleotide-reductase-encoding genes Infection and Immunity 71 : 6124-31,2003.
Dahl JL, Kraus CN, Boshoff HIM, Doan B, Foley K, Avarbock D, Kaplan G, Mizrahi V, Rubin H, Barry CE III: The role of RelMtb-mediated adaptation to stationary phase in long-term persistence of Mycobacterium tuberculosis in mice Proc Natl Acad Sci USA 100 : 10026-10031,2003.
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