Antibiotic resistant bacterial infections caused by both Gram-positive and Gram-negative pathogens pose a serious threat to human health. Resistance is increasing while research into new antibiotics and possible new targets is lagging. Both Gram-positive and Gram-negative bacteria are surrounded by a cross-linked carbohydrate polymer, peptidoglycan, which is conserved in all bacteria. This polymer is essential for bacterial survival because it stabilizes the cell membrane against high internal osmotic pressures. Peptidoglycan biosynthesis is a major target for antibiotics because interfering with this process leads to cell lysis. This research is directed towards understanding the mechanisms of action of vancomycin, penicillin, and moenomycin, important antibiotics that represent three classes of antibiotics that inhibit peptidoglycan synthesis. To understand the biological mechanisms of these drugs, an integrated program involving synthetic organic chemistry, biochemical and microbiological assays, structural studies, and bacterial genetics will be employed. A better understanding of how these drugs kill might lead to therapeutic strategies to improve their spectrum of activity and make them more effective at killing resistant microorganisms. Since these compounds target a fundamental metabolic process in bacteria, a better understanding of this process could lead to new antibiotic targets or strategies as well.

Public Health Relevance

Resistance to common antibiotics poses a serious threat to public health. The research proposed here is directed towards understanding the mechanism of action of three classes of antibiotics that inhibit bacterial cell wall synthesis. A better understanding of how these drugs kill might lead to therapeutic strategies to improve their spectrum of activity and make them more effective at killing resistant microorganisms.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM066174-11
Application #
8286257
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Fabian, Miles
Project Start
2002-07-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
11
Fiscal Year
2012
Total Cost
$632,899
Indirect Cost
$247,189
Name
Harvard University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
082359691
City
Cambridge
State
MA
Country
United States
Zip Code
02138
Qiao, Yuan; Lebar, Matthew D; Schirner, Kathrin et al. (2014) Detection of lipid-linked peptidoglycan precursors by exploiting an unexpected transpeptidase reaction. J Am Chem Soc 136:14678-81
Lupoli, Tania J; Lebar, Matthew D; Markovski, Monica et al. (2014) Lipoprotein activators stimulate Escherichia coli penicillin-binding proteins by different mechanisms. J Am Chem Soc 136:52-5
Sherman, David J; Lazarus, Michael B; Murphy, Lea et al. (2014) Decoupling catalytic activity from biological function of the ATPase that powers lipopolysaccharide transport. Proc Natl Acad Sci U S A 111:4982-7
Lebar, Matthew D; May, Janine M; Meeske, Alexander J et al. (2014) Reconstitution of peptidoglycan cross-linking leads to improved fluorescent probes of cell wall synthesis. J Am Chem Soc 136:10874-7
Lebar, Matthew D; Lupoli, Tania J; Tsukamoto, Hirokazu et al. (2013) Forming cross-linked peptidoglycan from synthetic gram-negative Lipid II. J Am Chem Soc 135:4632-5
Gampe, Christian M; Tsukamoto, Hirokazu; Doud, Emma H et al. (2013) Tuning the moenomycin pharmacophore to enable discovery of bacterial cell wall synthesis inhibitors. J Am Chem Soc 135:3776-9
Sherman, David J; Okuda, Suguru; Denny, William A et al. (2013) Validation of inhibitors of an ABC transporter required to transport lipopolysaccharide to the cell surface in Escherichia coli. Bioorg Med Chem 21:4846-51
Leiman, Sara A; May, Janine M; Lebar, Matthew D et al. (2013) D-amino acids indirectly inhibit biofilm formation in Bacillus subtilis by interfering with protein synthesis. J Bacteriol 195:5391-5
Lupoli, Tania J; Tsukamoto, Hirokazu; Doud, Emma H et al. (2011) Transpeptidase-mediated incorporation of D-amino acids into bacterial peptidoglycan. J Am Chem Soc 133:10748-51
Tsukamoto, Hirokazu; Kahne, Daniel (2011) N-methylimidazolium chloride-catalyzed pyrophosphate formation: application to the synthesis of Lipid I and NDP-sugar donors. Bioorg Med Chem Lett 21:5050-3

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