The design, synthesis, and evaluation of key analogs of the glycopeptide antibiotics including vancomycin 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 redesign vancomycin for dual binding to D-Ala-D-Ala and D-Ala-D-Lac to address the emerging bacterial resistance derived from peptidoglycan remodeling of D-Ala-D-Ala, combine successful pocket modified residue 4 analogs with additional peripheral modifications to enhance potency and in vivo efficacy, simplify the core aglycon structure, prepare successful residue 4 modified analogs by semisynthetic and fermentation methods, define and optimize the role of the aryl chlorides, and further explore a new class of glycopeptide derivatives we discovered that are active against VanB resistant bacteria. These studies will establish the consequences of re-engineering vancomycin to bind D-Ala-D-Lac, provide several unique approaches to countering the emerging vancomycin resistance, chart a rational path forward for the development of durable antibiotics for the treatment resistant bacterial infections including MRSA and the feared vancomycin-resistant bacteria (VRSA, VRE), and 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 establish key structural features contributing to transglycosylase inhibition and antimicrobial activity. Extensions of recently completed studies on the total synthesis of the chloropeptins (anti HIV activity) to an examination of their structure-function properties will be initiated.

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 biologically active natural products with their biological targets will be developed.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Synthetic and Biological Chemistry B Study Section (SBCB)
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Fu, Yali
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Scripps Research Institute
La Jolla
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Wu, Zhi-Chen; Isley, Nicholas A; Boger, Dale L (2018) N-Terminus Alkylation of Vancomycin: Ligand Binding Affinity, Antimicrobial Activity, and Site-Specific Nature of Quaternary Trimethylammonium Salt Modification. ACS Infect Dis 4:1468-1474
Okano, Akinori; Isley, Nicholas A; Boger, Dale L (2017) Peripheral modifications of [?[CH2NH]Tpg4]vancomycin with added synergistic mechanisms of action provide durable and potent antibiotics. Proc Natl Acad Sci U S A 114:E5052-E5061
Okano, Akinori; Isley, Nicholas A; Boger, Dale L (2017) Total Syntheses of Vancomycin-Related Glycopeptide Antibiotics and Key Analogues. Chem Rev 117:11952-11993
Boger, Dale L (2017) The Difference a Single Atom Can Make: Synthesis and Design at the Chemistry-Biology Interface. J Org Chem 82:11961-11980
Okano, Akinori; Nakayama, Atsushi; Wu, Kejia et al. (2015) Total syntheses and initial evaluation of [?[C(?S)NH]Tpg?]vancomycin, [?[C(?NH)NH]Tpg?]vancomycin, [?[CH?NH]Tpg?]vancomycin, and their (4-chlorobiphenyl)methyl derivatives: synergistic binding pocket and peripheral modifications for the glycopeptide antib 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
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
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
Nakayama, Atsushi; Okano, Akinori; Feng, Yiqing et al. (2014) Enzymatic glycosylation of vancomycin aglycon: completion of a total synthesis of vancomycin and N- and C-terminus substituent effects of the aglycon substrate. Org Lett 16:3572-5
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

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