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9 results on '"Johny, Chinchu"'

3. Structure–Activity Relationships of the MEPicides: N-Acyl and O-Linked Analogs of FR900098 as Inhibitors of Dxr from Mycobacterium tuberculosis and Yersinia pestis

Author

San Jose, Géraldine, primary, Jackson, Emily R., additional, Haymond, Amanda, additional, Johny, Chinchu, additional, Edwards, Rachel L., additional, Wang, Xu, additional, Brothers, R. Carl, additional, Edelstein, Emma K., additional, Odom, Audrey R., additional, Boshoff, Helena I., additional, Couch, Robin D., additional, and Dowd, Cynthia S., additional

Published
2016
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4. Synthesis and Bioactivity of beta-Substituted Fosmidomycin Analogues Targeting 1-Deoxy-D-xylulose-5-phosphate Reductoisomerase

Author

Chofor, Rene, Sooriyaarachchi, Sanjeewani, Risseeuw, Martijn D. P., Bergfors, Terese, Pouyez, Jenny, Johny, Chinchu, Haymond, Amanda, Everaert, Annelien, Dowd, Cynthia S., Maes, Louis, Coenye, Tom, Alex, Alexander, Couch, Robin D., Jones, T. Alwyn, Wouters, Johan, Mowbray, Sherry L., Van Calenbergh, Serge, Chofor, Rene, Sooriyaarachchi, Sanjeewani, Risseeuw, Martijn D. P., Bergfors, Terese, Pouyez, Jenny, Johny, Chinchu, Haymond, Amanda, Everaert, Annelien, Dowd, Cynthia S., Maes, Louis, Coenye, Tom, Alex, Alexander, Couch, Robin D., Jones, T. Alwyn, Wouters, Johan, Mowbray, Sherry L., and Van Calenbergh, Serge

Abstract

Blocking the 2-C-methyl-d-erythrithol-4-phosphate (MEP) pathway for isoprenoid biosynthesis offers interesting prospects for inhibiting Plasmodium or Mycobacterium spp. growth. Fosmidomycin (1) and its homologue FR900098 (2) potently inhibit 1-deoxy-d-xylulose-5-phosphate reductoisomerase (Dxr), a key enzyme in this pathway. Here we introduced aryl or aralkyl substituents at the beta-position of the hydroxamate analogue of 2. While direct addition of a beta-aryl moiety resulted in poor inhibition, longer linkers between the carbon backbone and the phenyl ring were generally associated with better binding to the enzymes. X-ray structures of the parasite Dxr-inhibitor complexes show that the longer compounds generate a substantially different flap structure, in which a key tryptophan residue is displaced, and the aromatic group of the ligand lies between the tryptophan and the hydroxamates methyl group. Although the most promising new Dxr inhibitors lack activity against Escherichia coli and Mycobacterium smegmatis, they proved to be highly potent inhibitors of Plasmodium falciparum in vitro growth.

Published
2015
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5. Synthesis and Bioactivity of β-Substituted Fosmidomycin Analogues Targeting 1-Deoxy-d-xylulose-5-phosphate Reductoisomerase

Author

Chofor, René, primary, Sooriyaarachchi, Sanjeewani, additional, Risseeuw, Martijn D. P., additional, Bergfors, Terese, additional, Pouyez, Jenny, additional, Johny, Chinchu, additional, Haymond, Amanda, additional, Everaert, Annelien, additional, Dowd, Cynthia S., additional, Maes, Louis, additional, Coenye, Tom, additional, Alex, Alexander, additional, Couch, Robin D., additional, Jones, T. Alwyn, additional, Wouters, Johan, additional, Mowbray, Sherry L., additional, and Van Calenbergh, Serge, additional

Published
2015
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6. Kinetic Characterization and Allosteric Inhibition of the Yersinia pestis 1-Deoxy-D-Xylulose 5-Phosphate Reductoisomerase (MEP Synthase)

Author

Haymond, Amanda, primary, Johny, Chinchu, additional, Dowdy, Tyrone, additional, Schweibenz, Brandon, additional, Villarroel, Karen, additional, Young, Richard, additional, Mantooth, Clark J., additional, Patel, Trishal, additional, Bases, Jessica, additional, Jose, Geraldine San, additional, Jackson, Emily R., additional, Dowd, Cynthia S., additional, and Couch, Robin D., additional

Published
2014
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8. Design of potential bisubstrate inhibitors against Mycobacterium tuberculosis (Mtb) 1-deoxy-d-xylulose 5-phosphate reductoisomerase (Dxr)—evidence of a novel binding mode

Author

San Jose, Géraldine, primary, Jackson, Emily R., additional, Uh, Eugene, additional, Johny, Chinchu, additional, Haymond, Amanda, additional, Lundberg, Lindsay, additional, Pinkham, Chelsea, additional, Kehn-Hall, Kylene, additional, Boshoff, Helena I., additional, Couch, Robin D., additional, and Dowd, Cynthia S., additional

Published
2013
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9. Kinetic Characterization and Allosteric Inhibition of the Yersinia pestis 1-Deoxy-D-Xylulose 5-Phosphate Reductoisomerase (MEP Synthase).

Author

Haymond, Amanda, Johny, Chinchu, Dowdy, Tyrone, Schweibenz, Brandon, Villarroel, Karen, Young, Richard, Mantooth, Clark J., Patel, Trishal, Bases, Jessica, Jose, Geraldine San, Jackson, Emily R., Dowd, Cynthia S., and Couch, Robin D.

Subjects
*YERSINIA pestis, *ALLOSTERIC enzymes, *BACTERIAL enzymes, *ISOMERASES, *ENZYME kinetics
Abstract

The methylerythritol phosphate (MEP) pathway found in many bacteria governs the synthesis of isoprenoids, which are crucial lipid precursors for vital cell components such as ubiquinone. Because mammals synthesize isoprenoids via an alternate pathway, the bacterial MEP pathway is an attractive target for novel antibiotic development, necessitated by emerging antibiotic resistance as well as biodefense concerns. The first committed step in the MEP pathway is the reduction and isomerization of 1-deoxy-D-xylulose-5-phosphate (DXP) to methylerythritol phosphate (MEP), catalyzed by MEP synthase. To facilitate drug development, we cloned, expressed, purified, and characterized MEP synthase from Yersinia pestis. Enzyme assays indicate apparent kinetic constants of KMDXP = 252 µM and KMNADPH = 13 µM, IC50 values for fosmidomycin and FR900098 of 710 nM and 231 nM respectively, and Ki values for fosmidomycin and FR900098 of 251 nM and 101 nM respectively. To ascertain if the Y. pestis MEP synthase was amenable to a high-throughput screening campaign, the Z-factor was determined (0.9) then the purified enzyme was screened against a pilot scale library containing rationally designed fosmidomycin analogs and natural product extracts. Several hit molecules were obtained, most notably a natural product allosteric affector of MEP synthase and a rationally designed bisubstrate derivative of FR900098 (able to associate with both the NADPH and DXP binding sites in MEP synthase). It is particularly noteworthy that allosteric regulation of MEP synthase has not been described previously. Thus, our discovery implicates an alternative site (and new chemical space) for rational drug development. [ABSTRACT FROM AUTHOR]

Published
2014
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