In recent years, the evolution of antibiotic-resistant bacteria has led to growing concerns among the medical community regarding the long-term effectiveness of our current arsenal of small-molecule inhibitors for treating pathogenic diseases. In response to this looming public health threat, researchers have initiated programs aimed at the design and development of architecturally novel chemotherapeutic agents with the goal of identifying molecules that may display enhanced biological profiles. Not surprisingly, natural products and their derivatives have emerged as leading candidates for this purpose owing to their striking array of biological properties as well as their historical influence in the development of modern-day medicines. Many of these secondary metabolites are adorned with carbohydrate residues that have been demonstrated to have a crucial role in orchestrating the biological activity of the parent glycoconjugate. Interestingly, while C-aryl glycosidic linkages are prevalent structural motifs among biologically active natural products, these compounds have received little attention compared to their O-glycoside counterparts in the search for new and more effective medicinal compounds. Recently, researchers have begun to exploit the intimate association between the sugar residues of a natural product and its associated biological efficacy in a process termed glycodiversification. In this methodology, the oligosaccharide domain of secondary metabolites is systematically altered and the resulting analogues are assayed for activity with the prospect of producing architecturally novel analogues with more potent and diverse biological profiles. As part of our program aimed at the development of C-aryl glycoside containing secondary metabolites as structurally novel antibiotics, we envision the following long-term goals:
Aim 1 Construction of a carbohydrate-derived ketene acetal phosphate library;
Aim 2 Glycodiversification of the angucycline antibiotic galtamycin aromatic scaffold using the ketene acetal phosphate library constructed in Aim 1 employing a Suzuki-Miyaura cross-coupling reaction;
and Aim 3 Biological evaluation of the galtamycin analogues produced in Aim 2 against various Gram-positive and Gram-negative bacteria cell lines.

Public Health Relevance

In recent years, the evolution of antibiotic-resistant bacteria has led to growing concerns among the medical community regarding the long-term effectiveness of our current arsenal of clinically prescribed medicines. The research outlined in this proposal is aimed at the design and development of structurally novel antibacterial compounds as potential drug candidates to help combat the increasing pervasiveness of multidrug resistant pathogens.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Academic Research Enhancement Awards (AREA) (R15)
Project #
7R15AI084075-02
Application #
8130394
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Xu, Zuoyu
Project Start
2009-07-01
Project End
2014-06-30
Budget Start
2010-06-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2009
Total Cost
$170,014
Indirect Cost
Name
University of the South
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
042939447
City
Sewanee
State
TN
Country
United States
Zip Code
37375
Hoffman, J Mason; Miller, Justin N; Gardner, Margaret E et al. (2014) Synthesis of N,N-Diethylbenzamides via a Non-Classical Mitsunobu Reaction. Synth Commun 44:976-980
Miller, Justin N; Pongdee, Rongson (2013) An efficient and cost-effective preparation of di-O-acetyl-D-rhamnal. Tetrahedron Lett 54:3185-3187
Leidy, Michelle R; Hoffman, J Mason; Pongdee, Rongson (2013) Preparation of C-arylglycals via Suzuki-Miyaura cross-coupling of dihydropyranylphosphates. Tetrahedron Lett 54:6889-6891