The synthesis and evaluation of key analogs of the glycopeptide antibiotics including vancomycin, teicoplanin, and ristocetin are detailed in efforts that will have a fundamental impact on the understanding and treatment of resistant bacterial infections (e.g. MRSA, VRSA, and VRE). This includes efforts to re-engineer vancomycin to bind D-Ala-D-Lac to address the emerging bacterial resistance derived from peptidoglycan remodeling of D-Ala-D-Ala, efforts to define and optimize the role of the aryl chlorides, and the full exploration of a new class of glycopeptide derivatives discovered in the last grant period that are active against VanB and VanA resistant bacteria. These studies should establish the feasibility of re-engineering vancomycin to bind D-Ala-D-Lac, may provide several unique approaches to countering the emerging vancomycin resistance, and will provide a fundamental understanding of the structure-function relationships of the glycopeptide antibiotics. An exciting complement to these studies is the detailed exploration of ramoplanin that is similarly designed to refine the understanding of its mechanism of action, define the structural details of its binding to lipid II, and to establish key structural features contributing to tranglycosylase inhibition and antimicrobial activity. Extensions of these studies for the total synthesis of chloropeptin I and II (anti HIV activity) are now nearly complete (both 1st and 2nd generation total syntheses completed) and the efforts are in the final stages of also providing complestatin A and B.

Public Health Relevance

Fundamentally new approaches and new therapeutics for the treatment of resistant bacterial infections including MRSA, VRSA, and VRE will emerge from the studies and a fundamental understanding of the mechanism of action and the interaction of the biologically active natural products with their biological targets will be developed.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA041101-27
Application #
8209090
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Misra, Raj N
Project Start
1997-06-01
Project End
2014-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
27
Fiscal Year
2012
Total Cost
$375,123
Indirect Cost
$177,586
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Okano, Akinori; Nakayama, Atsushi; Wu, Kejia et al. (2015) Total syntheses and initial evaluation of [Ψ[C(═S)NH]Tpg⁴]vancomycin, [Ψ[C(═NH)NH]Tpg⁴]vancomycin, [Ψ[CH₂NH]Tpg⁴]vancomycin, and their (4-chlorobiphenyl)methyl derivatives: synergistic binding pocket and peripheral modifications for the gly J Am Chem Soc 137:3693-704
Lee, Kiyoun; Poudel, Yam B; Glinkerman, Christopher M et al. (2015) Total synthesis of dihydrolysergic acid and dihydrolysergol: development of a divergent synthetic strategy applicable to rapid assembly of D-ring analogs. Tetrahedron 71:5897-5905
Okano, Akinori; Nakayama, Atsushi; Schammel, Alex W et al. (2014) Total synthesis of [Ψ[C(═NH)NH]Tpg(4)]vancomycin and its (4-chlorobiphenyl)methyl derivative: impact of peripheral modifications on vancomycin analogues redesigned for dual D-Ala-D-Ala and D-Ala-D-Lac binding. J Am Chem Soc 136:13522-5
Hou, L; Jiang, J; Liu, B et al. (2014) Association between smoking and deaths due to colorectal malignant carcinoma: a national population-based case-control study in China. Br J Cancer 110:1351-8
Pinchman, Joseph R; Boger, Dale L (2013) Probing the role of the vancomycin e-ring aryl chloride: selective divergent synthesis and evaluation of alternatively substituted E-ring analogues. J Med Chem 56:4116-24
Breazzano, Steven P; Poudel, Yam B; Boger, Dale L (2013) A Pd(0)-mediated indole (macro)cyclization reaction. J Am Chem Soc 135:1600-6
Pinchman, Joseph R; Boger, Dale L (2013) Investigation into the functional impact of the vancomycin C-ring aryl chloride. Bioorg Med Chem Lett 23:4817-9
Xie, Jian; Okano, Akinori; Pierce, Joshua G et al. (2012) Total synthesis of [ýý[C(ýýýS)NH]Tpg4]vancomycin aglycon, [ýý[C(ýýýNH)NH]Tpg4]vancomycin aglycon, and related key compounds: reengineering vancomycin for dual D-Ala-D-Ala and D-Ala-D-Lac binding. J Am Chem Soc 134:1284-97
Okano, Akinori; James, Robert C; Pierce, Joshua G et al. (2012) Silver(I)-promoted conversion of thioamides to amidines: divergent synthesis of a key series of vancomycin aglycon residue 4 amidines that clarify binding behavior to model ligands. J Am Chem Soc 134:8790-3
Pelisch, Federico; Khauv, Davitte; Risso, Guillermo et al. (2012) Involvement of hnRNP A1 in the matrix metalloprotease-3-dependent regulation of Rac1 pre-mRNA splicing. J Cell Biochem 113:2319-29

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