Gram-positive bacterial pathogens inflict an enormous burden of human disease world-wide. This closely related group of microbes includes Bacillus anthracis, the most notorius bioterror agent, as well as Staphylococcus aureus, which, judged by human morbidity, is currently the single most important infectious agent in the United States. Broad dissemination of antibiotic (methicillin) resistant S. aureus (MRSA) strains in American communities implies the return of the pre-antibiotic era unless new therapies can reduce human mortality. B. anthracis has been weaponized and engineered to acquire antibiotic resistance traits that render currently available antibiotics ineffective and human populations defenseless, if they had been exposed to drug-resistant anthrax spores. The GLRCE Research Project 3 proposal addresses the need for new antibiotics by unraveling molecular mechanisms that lead to assembly of siderophores, proteins, capsules or teichoic acids in the cell wall envelope of B. anthracis and S. aureus. Biosynthesis of all four types of compounds is either essential for bacterial growth or absolutely required for the pathogenesis of infection. An interdisciplinary team of researchers at Argonne National Laboratory, the University of Michigan and the University of Chicago applies multiple different technological platforms to focus on these questions: bioinformatics, molecular genetics, biochemical purification and assay development, structure determination, organic chemistry and small molecule inhibition, as well as infectious disease modeling. Products of this research are the in depth molecular appreciation of envelope function and pathogenesis in B. anthracis and S. aureus and the identification of small molecule inhibitors that will be tested for their property of antiinfective or antibiotic therapies.
The specific aims are: 1. Inhibition of capsular biosynthesis in Bacillus anthracis;2. Inhibition of lipoteichoic acid biosynthesis in Bacillus anthracis and MRSA;3. Inhibition of iron siderophore biosynthetic pathways in Bacillus anthracis and MRSA;4. Inhibition of protein assembly pathways in the envelope of Bacillus anthracis and MRSA;5. Inhibition of siderophore amide hydrolases in B. anthracis and MRSA.

Public Health Relevance

The GLRCE Research Project 3 proposal addresses the need for new antibiotics by unraveling molecular mechanisms that lead to assembly of siderophores, proteins, capsules or teichoic acids in the cell wall envelope of B. anthracis and S. aureus. Biosynthesis of all four types of compounds is either essential for bacterial growth or absolutely required for the pathogenesis of infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54AI057153-08
Application #
8233340
Study Section
Special Emphasis Panel (ZAI1)
Project Start
2011-03-01
Project End
2014-02-28
Budget Start
2011-03-01
Budget End
2012-02-29
Support Year
8
Fiscal Year
2011
Total Cost
$545,577
Indirect Cost
Name
University of Chicago
Department
Type
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Sloup, Rudolph E; Konal, Ashley E; Severin, Geoffrey B et al. (2017) Cyclic Di-GMP and VpsR Induce the Expression of Type II Secretion in Vibrio cholerae. J Bacteriol 199:
Chen, Grischa Y; McDougal, Courtney E; D'Antonio, Marc A et al. (2017) A Genetic Screen Reveals that Synthesis of 1,4-Dihydroxy-2-Naphthoate (DHNA), but Not Full-Length Menaquinone, Is Required for Listeria monocytogenes Cytosolic Survival. MBio 8:
Coulson, Garry B; Johnson, Benjamin K; Zheng, Huiqing et al. (2017) Targeting Mycobacterium tuberculosis Sensitivity to Thiol Stress at Acidic pH Kills the Bacterium and Potentiates Antibiotics. Cell Chem Biol 24:993-1004.e4
Hollands, Andrew; Corriden, Ross; Gysler, Gabriela et al. (2016) Natural Product Anacardic Acid from Cashew Nut Shells Stimulates Neutrophil Extracellular Trap Production and Bactericidal Activity. J Biol Chem 291:13964-73
Kuhn, Misty L; Alexander, Evan; Minasov, George et al. (2016) Structure of the Essential Mtb FadD32 Enzyme: A Promising Drug Target for Treating Tuberculosis. ACS Infect Dis 2:579-591
Duckworth, Benjamin P; Wilson, Daniel J; Aldrich, Courtney C (2016) Measurement of Nonribosomal Peptide Synthetase Adenylation Domain Activity Using a Continuous Hydroxylamine Release Assay. Methods Mol Biol 1401:53-61
Park, Sung Ryeol; Tripathi, Ashootosh; Wu, Jianfeng et al. (2016) Discovery of cahuitamycins as biofilm inhibitors derived from a convergent biosynthetic pathway. Nat Commun 7:10710
Agostoni, Marco; Waters, Christopher M; Montgomery, Beronda L (2016) Regulation of biofilm formation and cellular buoyancy through modulating intracellular cyclic di-GMP levels in engineered cyanobacteria. Biotechnol Bioeng 113:311-9
Völlger, Lena; Akong-Moore, Kathryn; Cox, Linda et al. (2016) Iron-chelating agent desferrioxamine stimulates formation of neutrophil extracellular traps (NETs) in human blood-derived neutrophils. Biosci Rep 36:
Le, J; Dam, Q; Schweizer, M et al. (2016) Effects of vancomycin versus nafcillin in enhancing killing of methicillin-susceptible Staphylococcus aureus causing bacteremia by human cathelicidin LL-37. Eur J Clin Microbiol Infect Dis 35:1441-7

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