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.
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.
|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|
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