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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Synthetic and Biological Chemistry A Study Section (SBCA)
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Misra, Raj N
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Scripps Research Institute
La Jolla
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Okano, Akinori; Nakayama, Atsushi; Schammel, Alex W et al. (2014) Total synthesis of [?[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
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
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
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
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
James, Robert C; Pierce, Joshua G; Okano, Akinori et al. (2012) Redesign of glycopeptide antibiotics: back to the future. ACS Chem Biol 7:797-804
Xie, Jian; Pierce, Joshua G; James, Robert C et al. (2011) A redesigned vancomycin engineered for dual D-Ala-D-ala And D-Ala-D-Lac binding exhibits potent antimicrobial activity against vancomycin-resistant bacteria. J Am Chem Soc 133:13946-9
Breazzano, Steven P; Boger, Dale L (2011) Synthesis and stereochemical determination of complestatin A and B (neuroprotectin A and B). J Am Chem Soc 133:18495-502
Shimamura, Hiroyuki; Breazzano, Steven P; Garfunkle, Joie et al. (2010) Total synthesis of complestatin: development of a Pd(0)-mediated indole annulation for macrocyclization. J Am Chem Soc 132:7776-83
Crane, Christine M; Pierce, Joshua G; Leung, Siegfried S F et al. (2010) Synthesis and evaluation of selected key methyl ether derivatives of vancomycin aglycon. J Med Chem 53:7229-35

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