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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
7R01AI059327-04
Application #
7516583
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Tseng, Christopher K
Project Start
2004-12-01
Project End
2009-11-30
Budget Start
2007-09-01
Budget End
2007-11-30
Support Year
4
Fiscal Year
2007
Total Cost
$202,618
Indirect Cost
Name
Indiana University Bloomington
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
006046700
City
Bloomington
State
IN
Country
United States
Zip Code
47401
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
Tocheva, Elitza I; Lopez-Garrido, Javier; Hughes, H Velocity et al. (2013) Peptidoglycan transformations during Bacillus subtilis sporulation. Mol Microbiol 88:673-86
Pilhofer, Martin; Aistleitner, Karin; Biboy, Jacob et al. (2013) Discovery of chlamydial peptidoglycan reveals bacteria with murein sacculi but without FtsZ. Nat Commun 4:2856
Kuru, Erkin; Hughes, H Velocity; Brown, Pamela J et al. (2012) In?Situ probing of newly synthesized peptidoglycan in live bacteria with fluorescent D-amino acids. Angew Chem Int Ed Engl 51:12519-23
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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