| The emergence of antibiotic resistance in pathogenic bacteria poses a major threat to human health, necessitating the development of new antibiotics. Most broad-spectrum antibiotics target one of several highly conserved bacterial pathways, which include DNA synthesis, folate metabolism, protein synthesis, and peptidoglycan synthesis. Our laboratory is studying the mechanisms of action of natural product antibiotics that target peptidoglycan biosynthesis, including moenomycin and ramoplanin. Both of these compounds inhibit the transglycosylation step of peptidoglycan biosynthesis, but by different mechanisms. Ramoplanin binds to Lipid II, the substrate of the transglycosylases, whereas moenomycin binds directly to the enzymes. We have developed approaches to dissect the mechanism of ramoplanin. These approaches should be applicable to other substrate-binding antibiotics. We are now working towards understanding moenomycin with the expectation that a better understanding of how this molecule functions will lead to new antibiotics that target the transglycosylation step of peptidoglycan biosynthesis.
We have also begun to study the biosynthetic machinery responsible for the production of moenomycin. Access to moenomycin analogs, obtained by manipulating the biosynthetic pathway, could be useful for understanding the activity of the parent compound. Our primary motivation for studying moenomycin biosynthesis, however, is that the molecule has an unusual structure and its biosynthesis could not be predicted based on what is known about the biosynthesis of other antibiotics. We recently identified the moenomycin gene cluster in the producing strain Streptomyces ghanaensis, and are now deconvoluting the molecular logic by which this unusual antibiotic is synthesized using a combination of genetics and biochemistry.
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"The Mechanism of Action of Ramoplanin and Enduracidin" Fang X, Tiyanont K, Zhang Y, Boger D, and Walker S. Molecular Biosystems, 2006;2:69-76.
"In Vitro Reconstitution of EryCIII Activity for the Preparation of Unnatural Macrolides" Yuan Y, Chung HS, Leimkuhler C, Walsh CT, Kahne D, and Walker S. J Am Chem Soc 2005;127:14128-14129.
"Chemistry and Biology of Ramoplanin: a Lipoglycodepsipeptide with Potent Antibiotic Activity" Walker S, Hu Y, Chen L, Rew Y, Shin D, and Boger DL, Chem. Rev. 2005;105:425-448.
"Differential Inhibition of S. aureus PBP2 by Glycopeptide Antibiotics" Leimkuhler C, Chen L, Barrett D, Panzone G, Sun B, Falcone B, Donadio S, Walker S, Kahne D.J. Am. Chem. Soc. 2005;127:3250-3251.
"Reconstitution and Characterization of a New Desosaminyl Transferase, EryCIII, from the Erythromycin Biosynthetic Pathway" Lee HY, Chung HS, Hang C, Khosla C, Walsh CT, Kahne D, Walker S. J. Am. Chem. Soc. 2004; 126:9924-9925.
"Dissecting Ramoplanin: Mechanistic Analysis of Synthetic Ramoplanin Analogues as a Guide to the Design of Improved Antibiotics" Chen L, Yuan Y, Helm JS, Hu Y, Rew Y, Shin D, Boger DL, Walker S. J. Am. Chem. Soc. 2004; 126:7462-7463.
"Vancomycin Analogs Active Against VanA Strains Inhibit Bacterial Transglycosylase Without Binding Substrate" Chen L, Walker D, Sun B, Hu Y, Walker S, Kahne D. Proc. Natl. Acad. Sci. USA, 2003; 100:5658-5663.
"Ramoplanin Inhibits Bacterial Transglycosylases by Binding as a Dimer to Lipid II" Hu Y, Helm JS, Chen L, Ye X-Y, Walker S. J. Am. Chem. Soc. 2003; 125:8736-8737.
"Rethinking Ramoplanin: The Role of Substrate Binding in Inhibition of Peptidogylcan Biosynthesis" Helm J, Chen L, Walker S. J. Am. Chem. Soc. 2002; 124:13970-13971.
"A New Structure for the Substrate-Binding Antibiotic Ramoplanin" Lo M, Helm JS, Sarngadharan G, Pelczer I, Walker S. J. Am. Chem. Soc. 2001; 123:8640-8641.
"A New Mechanism of Action Proposed for Ramoplanin" Lo M, Men H, Branstrom A, Helm J, Yao N, Goldman R, Walker S. J. Am. Chem. Soc.2000;122:3540-3541.
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