The development of drug-resistant strains of B. anthracis is technically quite feasible, and could be a substantial threat in future terrorist attacks. Building on a well-established collaborative network amongst the investigators participating in this project, we propose an integrated approach toward the development of new antimicrobials, new potentiators of existing antimicrobials, and direct inhibitors of the anthrax toxin as strategies to combat natural and bioengineered forms of B. anthracis. We will use a combination of strategies, beginning with genetic identification and validation of novel bacterial targets, determination of target 3D molecular structures, utilization of diverse chemical libraries for high throughput screening, structure-based drug design, synthesis of lead compounds and their optimization, followed by macrophage and animal testing. An important strength of the application is the broad range of the participants' expertise, including bacterial genetics and biochemistry, structural biology of macromolecules, computer-assisted drug design, synthetic chemistry, macrophage biology, animal modeling and clinical infectious disease. Project 1 will identify and validate new antibiotic targets in ribosomal RNA. Project 2 will identify and validate new infection-related targets in Bacillus anthracis. Project 3 will utilize structure-based design and high throughput screening to develop lead inhibitors of currently known and to-be-identified antibiotic targets. Project 4 will develop inhibitors to prevent the binding of the B. anthracis toxin to the cellular receptor. Project 5 will evaluate the role of antibiotics in modulating cytokine activation and toxin triggering following macrophage infection and animal model development. Four scientific cores will support these projects: A protein expression core will provide proteins for target evaluation and structure-based design. A macromolecular characterization and structure core will provide structural and thermodynamic information for target characterization and structure-based design. A chemical improvement core will provide synthetic design and optimization of lead inhibitors. A bioassay core will provide a variety of assays for identifying and evaluating lead therapeutic agents. An administrative core will provide fiscal management and administrative support.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Study Section
Special Emphasis Panel (ZAI1-GPJ-M (M1))
Program Officer
Breen, Joseph J
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University of Illinois at Chicago
Schools of Pharmacy
United States
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Tuntland, Micheal L; Fung, L W-M (2016) Substrate independent ATPase activity may complicate high throughput screening. Anal Biochem 510:18-20
Thomas, Johnson; Epshtein, Yulia; Chopra, Arun et al. (2011) Anthrax lethal factor activates K(+) channels to induce IL-1* secretion in macrophages. J Immunol 186:5236-43
Belousoff, Matthew J; Shapira, Tal; Bashan, Anat et al. (2011) Crystal structure of the synergistic antibiotic pair, lankamycin and lankacidin, in complex with the large ribosomal subunit. Proc Natl Acad Sci U S A 108:2717-22
Wubben, T; Mesecar, A D (2011) Structure of Mycobacterium tuberculosis phosphopantetheine adenylyltransferase in complex with the feedback inhibitor CoA reveals only one active-site conformation. Acta Crystallogr Sect F Struct Biol Cryst Commun 67:541-5
Wubben, Thomas J; Mesecar, Andrew D (2010) Kinetic, thermodynamic, and structural insight into the mechanism of phosphopantetheine adenylyltransferase from Mycobacterium tuberculosis. J Mol Biol 404:202-19
Auerbach, Tamar; Mermershtain, Inbal; Davidovich, Chen et al. (2010) The structure of ribosome-lankacidin complex reveals ribosomal sites for synergistic antibiotics. Proc Natl Acad Sci U S A 107:1983-8
Pegan, Scott D; Tian, Yang; Sershon, Valerie et al. (2010) A universal, fully automated high throughput screening assay for pyrophosphate and phosphate release from enzymatic reactions. Comb Chem High Throughput Screen 13:27-38
Samant, Shalaka; Hsu, Fong-Fu; Neyfakh, Alexander A et al. (2009) The Bacillus anthracis protein MprF is required for synthesis of lysylphosphatidylglycerols and for resistance to cationic antimicrobial peptides. J Bacteriol 191:1311-9
Mehboob, Shahila; Guo, Liang; Fu, Wentao et al. (2009) Glutamate racemase dimerization inhibits dynamic conformational flexibility and reduces catalytic rates. Biochemistry 48:7045-55
Pegan, Scott D; Rukseree, Kamolchanok; Franzblau, Scott G et al. (2009) Structural basis for catalysis of a tetrameric class IIa fructose 1,6-bisphosphate aldolase from Mycobacterium tuberculosis. J Mol Biol 386:1038-53

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