Antimicrobial agents that inhibit bacterial cell wall biosynthesis have dominated treatment regimens for the management of bacterial infections for over fifty years. Glycopeptide and beta-Iactam antibiotics derive their antibacterial activity through inhibition of keys steps in the cell wall biosynthesis cascade. Bacterial resistance to these antibiotics has now reached an alarming level and has underscored the urgent need for new chemotherapeutic agents to augment the cell wall active pharmacopeia. The objective of this proposal is the chemical synthesis of three very interesting peptide antibiotics (plusbacin As, katanosin B, and mersacidin) that show very promising antibacterial activity against vancomycin-resistant and methicillin-resistant Gram-positive pathogens. These agents exert their antibiotic action via inhibition of the late-stage reactions involved in peptidoglycan biosynthesis, believed to be the result of sequestration of lipid intermediates utilized in the biosynthetic reactions. We plan to utilize our expertise in the synthesis of cell wall intermediates in order to gain structural information on the antibiotic-lipid intermediate complexes. We will also measure binding affinity of the target compounds, and their derivatives, for various lipid intermediates and attempt to correlate affinity with antibacterial activity and enzyme inhibition. Information gained from these studies will provide valuable insights regarding the function of these agents and may provide a template for de novo design of future-generation antibacterials.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Medicinal Chemistry Study Section (MCHA)
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Tseng, Christopher K
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Indiana University Bloomington
Schools of Arts and Sciences
United States
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Kuru, Erkin; Tekkam, Srinivas; Hall, Edward et al. (2015) Synthesis of fluorescent D-amino acids and their use for probing peptidoglycan synthesis and bacterial growth in situ. Nat Protoc 10:33-52
Kim, Sung Joon; Singh, Manmilan; Wohlrab, Aaron et al. (2013) The isotridecanyl side chain of plusbacin-A3 is essential for the transglycosylase inhibition of peptidoglycan biosynthesis. Biochemistry 52:1973-9
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Garcia-Reynaga, Pablo; Vannieuwenhze, Michael S (2012) Biomimetic Synthesis of Cbz-(S)-Dolaphenine. Tetrahedron Lett 53:4989-4993
Hall, Edward A; Kuru, Erkin; VanNieuwenhze, Michael S (2012) Solid-phase synthesis of lysobactin (katanosin B): insights into structure and function. Org Lett 14:2730-3
Garcia-Reynaga, Pablo; Carrillo, Angela K; VanNieuwenhze, Michael S (2012) Decarbonylative approach to the synthesis of enamides from amino acids: stereoselective synthesis of the (Z)-aminovinyl-D-cysteine unit of mersacidin. Org Lett 14:1030-3
Carrillo, Angela K; VanNieuwenhze, Michael S (2012) Synthesis of the AviMeCys-containing D-ring of mersacidin. Org Lett 14:1034-7
Olivier, Kevin S; Van Nieuwenhze, Michael S (2010) Synthetic studies toward the mannopeptimycins: synthesis of orthogonally protected beta-hydroxyenduracididines. Org Lett 12:1680-3

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