Abstract

Antibiotic resistance has become a major problem in hospitals and in the community and we need new antibiotics to forestall a public health crisis. The research proposed here is directed towards understanding the molecular basis by which some glycopeptide derivatives overcome antibiotic resistance and towards understanding the mechanism of action of moenomycin, a potent antibiotic that inhibits a major but underexploited antibacterial target, the transglycosyalses. Efficient chemoenzymatic and synthetic routes to glycolipid derivatives and moenomycin analogues are proposed, and the compounds that are made will be tested in both cell-based and enzymological assays in order to provide insight into structure-activity relationships. We also propose experiments to understand the mechanistic basis for how glycopeptide analogues overcome vanA and vanB resistance. A better understanding of the mechanisms by which resistance can be overcome, combined with information on how activity varies as a function of structure, could lead to the development of new antibiotics that overcome common forms of antibiotic resistance.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM066174-08
Application #
7644827
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Fabian, Miles
Project Start
2002-07-01
Project End
2010-06-30
Budget Start
2009-07-01
Budget End
2010-06-30
Support Year
8
Fiscal Year
2009
Total Cost
$532,824
Indirect Cost

  Institution

Name
Harvard University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
082359691
City
Cambridge
State
MA
Country
United States
Zip Code
02138

  Publications

Bertani, Blake R; Taylor, Rebecca J; Nagy, Emma et al. (2018) A cluster of residues in the lipopolysaccharide exporter that selects substrate variants for transport to the outer membrane. Mol Microbiol 109:541-554
Mandler, Michael D; Baidin, Vadim; Lee, James et al. (2018) Novobiocin Enhances Polymyxin Activity by Stimulating Lipopolysaccharide Transport. J Am Chem Soc 140:6749-6753
Zheng, Sanduo; Sham, Lok-To; Rubino, Frederick A et al. (2018) Structure and mutagenic analysis of the lipid II flippase MurJ from Escherichia coli. Proc Natl Acad Sci U S A 115:6709-6714
Rubino, Frederick A; Kumar, Sujeet; Ruiz, Natividad et al. (2018) Membrane Potential Is Required for MurJ Function. J Am Chem Soc 140:4481-4484
Schaefer, Kaitlin; Owens, Tristan W; Kahne, Daniel et al. (2018) Substrate Preferences Establish the Order of Cell Wall Assembly in Staphylococcus aureus. J Am Chem Soc 140:2442-2445
Sherman, David J; Xie, Ran; Taylor, Rebecca J et al. (2018) Lipopolysaccharide is transported to the cell surface by a membrane-to-membrane protein bridge. Science 359:798-801
Xie, Ran; Taylor, Rebecca J; Kahne, Daniel (2018) Outer Membrane Translocon Communicates with Inner Membrane ATPase To Stop Lipopolysaccharide Transport. J Am Chem Soc 140:12691-12694
May, Janine M; Owens, Tristan W; Mandler, Michael D et al. (2017) The Antibiotic Novobiocin Binds and Activates the ATPase That Powers Lipopolysaccharide Transport. J Am Chem Soc 139:17221-17224
Moison, Eileen; Xie, Ran; Zhang, Ge et al. (2017) A Fluorescent Probe Distinguishes between Inhibition of Early and Late Steps of Lipopolysaccharide Biogenesis in Whole Cells. ACS Chem Biol 12:928-932
Welsh, Michael A; Taguchi, Atsushi; Schaefer, Kaitlin et al. (2017) Identification of a Functionally Unique Family of Penicillin-Binding Proteins. J Am Chem Soc 139:17727-17730

Showing the most recent 10 out of 59 publications