Design of antituberculosis agents that target siderophore biosynthesis

Summary

Principal Investigator: Courtney Aldrich
Affiliation: University of Minnesota
Country: USA
Abstract: DESCRIPTION (provided by applicant): Tuberculosis (TB) caused by the slow growing bacillus Mycobacterium tuberculosis (Mtb) is the leading cause of infectious disease mortality in the world by a bacterial pathogen. The mycobactins have been proposed as novel targets for TB drugs since these small-molecule iron-chelators (siderophores) produced by Mycobacterium tuberculosis (MTb) are responsible for obtaining iron from the human host, a process that is essential for the survival of MTb. Additionally, the mycobactins may serve as a short-term iron reservoir in Mtb. Inhibition of mycobactin biosynthesis is expected to block iron acquisition and potentially disrupt iron homeostasis. We propose to develop a new class of antibacterial agents that target siderophore biosynthesis. The primary focus of this application will be on the organism Mycobacterium tuberculosis;however, the Gram-negative Acinetobacter baumannii and Klebsiella pneumoniae will also be pursued. In the first specific aim we will build on our substantial knowledge of the structure activity relationships of our lead compound 5'-O-[N-(salicyl)sulfamoyl]adenosine (Sal-AMS) to improve drug disposition properties. Compounds will be investigated to determine pharmacokinetic properties and then evaluated in an in vivo model of infection using a murine model of TB. Additionally, we will explore 1) new analogues to confirm our hypothesized binding model, 2) analogues with an improved spectrum of antibacterial activity, and 3) a new series of nonnucleoside inhibitors identified from high-throughput screening. In the second specific aim, pharmacokinetic studies will be performed and compounds evaluated in a murine TB model. Newly synthesized analogues will also be assayed for enzyme inhibition, antibacterial activity, and drug disposition properties. In a final subaim, we propose to perform mechanism of action studies to identify potential off-target receptors targeted by our prototypical siderophore inhibitors. In the third specific aim, we propose to synthesize transitions-state inhibitors of a new enzyme, which catalyzes the first biosynthetic step in production of the siderophores from M. tuberculosis. These rationally designed inhibitors will be evaluated for enzyme inhibition, co-crystallized with the molecular target, evaluated for antitubercular activity and toxicity, and finally their mechanism of action will be explored using whole-cell radioassays. It is expected that upon completion of this we will have validated our hypothesis that siderophore-mediated iron acquisition is essential in vivo. Thus, the research proposed herein is expected to have a positive impact on human health and may additionally validate a new class of antibiotics that target siderophore biosynthesis. PUBLIC HEALTH RELEVANCE: Tuberculosis (TB) caused by the slow growing bacillus Mycobacterium tuberculosis (Mtb) is the leading cause of infectious disease mortality in the world by a bacterial pathogen. M. tuberculosis and other atypical mycobacteria are now classified as opportunistic infections of AIDS patients. The proposed research is expected to validate siderophore biosynthesis as new antibacterial target, which may lead to the development of a new class of antitubercular agents.
Funding Period: -------------------- - --------------------
more information: NIH RePORT

Top Publications

  1. pmc Design, synthesis, and biological evaluation of beta-ketosulfonamide adenylation inhibitors as potential antitubercular agents
    Jagadeshwar Vannada
    Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, Minnesota 55455, USA
    Org Lett 8:4707-10. 2006
  2. pmc Inhibitors of the salicylate synthase (MbtI) from Mycobacterium tuberculosis discovered by high-throughput screening
    Mahalakshmi Vasan
    Center for Drug Design, University of Minnesota, Minneapolis, 55455, USA
    ChemMedChem 5:2079-87. 2010
  3. pmc Total synthesis and biological evaluation of transvalencin Z
    Kathryn M Nelson
    Center for Drug Design, University of Minnesota, Minneapolis, Minnesota 55455, USA
    J Nat Prod 75:1037-43. 2012
  4. pmc Development of a selective activity-based probe for adenylating enzymes: profiling MbtA Involved in siderophore biosynthesis from Mycobacterium tuberculosis
    Benjamin P Duckworth
    Center for Drug Design and Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, United States
    ACS Chem Biol 7:1653-8. 2012
  5. pmc Characterization of AusA: a dimodular nonribosomal peptide synthetase responsible for the production of aureusimine pyrazinones
    Daniel J Wilson
    Center for Drug Design, University of Minnesota, Minneapolis, MN 55455, United States
    Biochemistry 52:926-37. 2013
  6. pmc Engineering the substrate specificity of the DhbE adenylation domain by yeast cell surface display
    Keya Zhang
    Department of Chemistry, University of Chicago, Chicago, IL 60637, USA
    Chem Biol 20:92-101. 2013
  7. pmc Non-nucleoside inhibitors of BasE, an adenylating enzyme in the siderophore biosynthetic pathway of the opportunistic pathogen Acinetobacter baumannii
    João Neres
    Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, Minnesota 55455, USA
    J Med Chem 56:2385-405. 2013
  8. pmc Synthesis of chromone, quinolone, and benzoxazinone sulfonamide nucleosides as conformationally constrained inhibitors of adenylating enzymes required for siderophore biosynthesis
    Curtis A Engelhart
    Center for Drug Design, University of Minnesota, Minneapolis, Minnesota 55455, USA
    J Org Chem 78:7470-81. 2013
  9. pmc Structure-activity relationships of 2-aminothiazoles effective against Mycobacterium tuberculosis
    Anja Meissner
    Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, MN 55455, USA
    Bioorg Med Chem 21:6385-97. 2013
  10. doi Reaction intermediate analogues as bisubstrate inhibitors of pantothenate synthetase
    Zhixiang Xu
    College of Pharmaceutical Science, Soochow University, Suzhou 215123, China
    Bioorg Med Chem 22:1726-35. 2014

Scientific Experts

  • Liqiang Chen
  • Courtney C Aldrich
  • Daniel J Wilson
  • João Neres
  • Clifton E Barry
  • Helena I Boshoff
  • Benjamin P Duckworth
  • Kathryn M Nelson
  • Eric M Bennett
  • Chunhua Qiao
  • Ravindranadh V Somu
  • Nicholas P Labello
  • Curtis A Engelhart
  • Andrew M Gulick
  • Mahalakshmi Vasan
  • Eric J Drake
  • Ce Shi
  • Amol Gupte
  • Jagadeshwar Vannada
  • Zhixiang Xu
  • Keya Zhang
  • Anja Meissner
  • Aaron M Teitelbaum
  • Alison L Sikora
  • Brian J Beck
  • Laura Celia
  • Yang Yu
  • Joanna Evans
  • Jinglei Chen
  • Wei Yin
  • Valerie Mizrahi
  • Leonardo K Martinelli
  • Peng Fu
  • Karan Bhuripanyo
  • Jun Yin
  • Bo Zhao
  • Kimberly D Grimes
  • Christine E Salomon
  • John S Blanchard
  • Rory P Remmel
  • Jessica Williams
  • David M Ferguson
  • Chengguo Xing

Detail Information

Publications25

  1. pmc Design, synthesis, and biological evaluation of beta-ketosulfonamide adenylation inhibitors as potential antitubercular agents
    Jagadeshwar Vannada
    Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, Minnesota 55455, USA
    Org Lett 8:4707-10. 2006
    ..Herein, we report efforts to refine this inhibitor scaffold by replacing the labile acylsulfamate linkage (highlighted) with the more chemically robust beta-ketosulfonamide linkage of 3 and 4...
  2. pmc Inhibitors of the salicylate synthase (MbtI) from Mycobacterium tuberculosis discovered by high-throughput screening
    Mahalakshmi Vasan
    Center for Drug Design, University of Minnesota, Minneapolis, 55455, USA
    ChemMedChem 5:2079-87. 2010
    ..Benzimidazole-2-thione 4 emerged as the most promising inhibitor owing to its potent reversible inhibition...
  3. pmc Total synthesis and biological evaluation of transvalencin Z
    Kathryn M Nelson
    Center for Drug Design, University of Minnesota, Minneapolis, Minnesota 55455, USA
    J Nat Prod 75:1037-43. 2012
    ..Surprisingly, none of the transvalencin Z diastereomers exhibited any inhibitory activity against a panel of microbial pathogens, including several species of mycobacteria...
  4. pmc Development of a selective activity-based probe for adenylating enzymes: profiling MbtA Involved in siderophore biosynthesis from Mycobacterium tuberculosis
    Benjamin P Duckworth
    Center for Drug Design and Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, United States
    ACS Chem Biol 7:1653-8. 2012
    ..Furthermore, this probe provides a prototypical core scaffold for the creation of ABPs to profile any of the other 66 adenylating enzymes in Mtb or the multitude of adenylating enzymes in other pathogenic bacteria...
  5. pmc Characterization of AusA: a dimodular nonribosomal peptide synthetase responsible for the production of aureusimine pyrazinones
    Daniel J Wilson
    Center for Drug Design, University of Minnesota, Minneapolis, MN 55455, United States
    Biochemistry 52:926-37. 2013
    ..AusA is a minimal autonomous two-module NRPS that represents an excellent model system for further kinetic and structural characterization...
  6. pmc Engineering the substrate specificity of the DhbE adenylation domain by yeast cell surface display
    Keya Zhang
    Department of Chemistry, University of Chicago, Chicago, IL 60637, USA
    Chem Biol 20:92-101. 2013
    ..Our study demonstrates that yeast display can be used as a high throughput selection platform to reprogram the "nonribosomal code" of A-domains...
  7. pmc Non-nucleoside inhibitors of BasE, an adenylating enzyme in the siderophore biosynthetic pathway of the opportunistic pathogen Acinetobacter baumannii
    João Neres
    Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, Minnesota 55455, USA
    J Med Chem 56:2385-405. 2013
    ..These results provide a foundation for future studies aimed at increasing both enzyme potency and antibacterial activity...
  8. pmc Synthesis of chromone, quinolone, and benzoxazinone sulfonamide nucleosides as conformationally constrained inhibitors of adenylating enzymes required for siderophore biosynthesis
    Curtis A Engelhart
    Center for Drug Design, University of Minnesota, Minneapolis, Minnesota 55455, USA
    J Org Chem 78:7470-81. 2013
    ..Mitsunobu coupling of these bicyclic sulfonamides with a protected adenosine derivative followed by global deprotection provides a concise synthesis of the respective inhibitors. ..
  9. pmc Structure-activity relationships of 2-aminothiazoles effective against Mycobacterium tuberculosis
    Anja Meissner
    Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, MN 55455, USA
    Bioorg Med Chem 21:6385-97. 2013
    ..However, 55 is rapidly metabolized by human liver microsomes (t1/2=28min) with metabolism occurring at the invariant aminothiazole moiety and Mtb develops spontaneous low-level resistance with a frequency of ∼10(-5). ..
  10. doi Reaction intermediate analogues as bisubstrate inhibitors of pantothenate synthetase
    Zhixiang Xu
    College of Pharmaceutical Science, Soochow University, Suzhou 215123, China
    Bioorg Med Chem 22:1726-35. 2014
    ..Finally, whole cell activity is assessed against wild-type Mtb as well as a PanC knockdown strain where PanC is depleted to less than 5% of wild-type levels. ..
  11. pmc Antitubercular nucleosides that inhibit siderophore biosynthesis: SAR of the glycosyl domain
    Ravindranadh V Somu
    Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, MN 55455, USA
    J Med Chem 49:7623-35. 2006
    ..Additionally, we report improved conditions for the expression of MbtA and biochemical analysis, demonstrating that MbtA follows a random sequential enzyme mechanism for the adenylation half-reaction...
  12. pmc A mechanism-based aryl carrier protein/thiolation domain affinity probe
    Chunhua Qiao
    Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, MN 55455, USA
    J Am Chem Soc 129:6350-1. 2007
  13. pmc 5'-O-[(N-acyl)sulfamoyl]adenosines as antitubercular agents that inhibit MbtA: an adenylation enzyme required for siderophore biosynthesis of the mycobactins
    Chunhua Qiao
    Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, MN 55455, USA
    J Med Chem 50:6080-94. 2007
    ....
  14. pmc Inhibition of siderophore biosynthesis in Mycobacterium tuberculosis with nucleoside bisubstrate analogues: structure-activity relationships of the nucleobase domain of 5'-O-[N-(salicyl)sulfamoyl]adenosine
    João Neres
    Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, Minnesota 55455, USA
    J Med Chem 51:5349-70. 2008
    ....
  15. pmc Inhibition of siderophore biosynthesis by 2-triazole substituted analogues of 5'-O-[N-(salicyl)sulfamoyl]adenosine: antibacterial nucleosides effective against Mycobacterium tuberculosis
    Amol Gupte
    Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, Minnesota 55455, USA
    J Med Chem 51:7495-507. 2008
    ..Additionally, the well-known valence tautomerism between 2-azidopurines and their fused tetrazole counterparts led to an unexpected facile acylation of the purine N-6 amino group...
  16. pmc Aryl acid adenylating enzymes involved in siderophore biosynthesis: fluorescence polarization assay, ligand specificity, and discovery of non-nucleoside inhibitors via high-throughput screening
    João Neres
    Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, Minnesota 55455, USA
    Biochemistry 47:11735-49. 2008
    ....
  17. pmc Quantitative three dimensional structure linear interaction energy model of 5'-O-[N-(salicyl)sulfamoyl]adenosine and the aryl acid adenylating enzyme MbtA
    Nicholas P Labello
    Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, Minnesota 55455, USA
    J Med Chem 51:7154-60. 2008
    ..The resulting model was further validated by chemical synthesis of a novel inhibitor with a predicted LIE binding affinity of 1.6 nM and a subsequently determined experimental K(i)(app) of 0.7 nM...
  18. pmc Efficient Pd-catalyzed coupling of tautomerizable heterocycles with terminal alkynes via C-OH bond activation using PyBrOP
    Ce Shi
    Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, Minnesota 55455, USA
    Org Lett 12:2286-9. 2010
    ....
  19. pmc Adenylating enzymes in Mycobacterium tuberculosis as drug targets
    Benjamin P Duckworth
    Center for Drug Design, University of Minnesota, Minneapolis, MN 55455, USA
    Curr Top Med Chem 12:766-96. 2012
    ..Additionally, the enzymes NadE, GuaA, PanC, and MshC involved in the respective synthesis of NAD, guanine, pantothenate, and mycothiol will be discussed as well as BirA that is responsible for biotinylation of the acyl CoA-carboxylases...
  20. pmc Biochemical and structural characterization of bisubstrate inhibitors of BasE, the self-standing nonribosomal peptide synthetase adenylate-forming enzyme of acinetobactin synthesis
    Eric J Drake
    Hauptman Woodward Institute and Department of Structural Biology, University at Buffalo, Buffalo, NY 14203 1102, USA
    Biochemistry 49:9292-305. 2010
    ..Structures of rationally designed bisubstrate inhibitors are also presented...
  21. pmc Kinetic and inhibition studies of dihydroxybenzoate-AMP ligase from Escherichia coli
    Alison L Sikora
    Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA
    Biochemistry 49:3648-57. 2010
    ..The tight binding of Sal-AMS and DHB-AMS to EntE suggests that these compounds may be developed further as effective antibiotics targeted to this enzyme...
  22. pmc Triazole-linked inhibitors of inosine monophosphate dehydrogenase from human and Mycobacterium tuberculosis
    Liqiang Chen
    Center for Drug Design, Academic Health Center, University of Minnesota, 516 Delaware Street SE, Minneapolis, Minnesota 55455, USA
    J Med Chem 53:4768-78. 2010
    ..Computational studies of these IMPDH enzymes helped rationalize the observed structure-activity relationships. Additionally, the first cloning, expression, purification and characterization of mtIMPDH is reported...