Abstract: With the advent of the """"""""""""""""age of antibiotics"""""""""""""""" in the 1940s, many believed that we had conquered these dangerous microbes. However, it quickly became apparent that the ability of bacteria to evolve resistance had been sorely underestimated and today, infectious diseases are the second-leading cause of death worldwide and the third-leading cause of mortality in economically advanced countries. The ever-growing and significant problem of antibacterial resistance requires discovery of new leads. However, identification of the next generations of antibiotics will necessitate a change in the curent drug discovery paradigm. Pursuit of compounds that function through the commonly targeted mechanisms of action will not yield the combination of antibiotic potency and long-term efficacy necessary to combat resistant organisms. In fact, compounds that attack microbes through multiple, simultaneous mechanisms will be essential to anti-infective development. Public Health Relevance: This program will improve public health through the identification of the next generation of antimicrobial therapeutic agents, particularly focusing on more effective and long-lifetime treatments for drug resistant infections. To achieve this goal, we will develop and apply technologies for the discovery of drug leads from nature's vast reservoir of antibacterial natural products from plants and microorganisms.

National Institute of Health (NIH)
Office of The Director, National Institutes of Health (OD)
NIH Director’s New Innovator Awards (DP2)
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Special Emphasis Panel (ZGM1-NDIA-S (01))
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Basavappa, Ravi
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Indiana University Bloomington
Schools of Arts and Sciences
United States
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Goswami, Manibarsha; Wilke, Kaelyn E; Carlson, Erin E (2017) Rational Design of Selective Adenine-Based Scaffolds for Inactivation of Bacterial Histidine Kinases. J Med Chem 60:8170-8182
Sharifzadeh, Shabnam; Boersma, Michael J; Kocaoglu, Ozden et al. (2017) Novel Electrophilic Scaffold for Imaging of Essential Penicillin-Binding Proteins in Streptococcus pneumoniae. ACS Chem Biol 12:2849-2857
Wilke, Kaelyn E; Carlson, Erin E (2016) Thiol-ene-Enabled Detection of Thiophosphorylation as a Labeling Strategy for Phosphoproteins. Methods Mol Biol 1355:3-15
Kocaoglu, Ozden; Carlson, Erin E (2016) Progress and prospects for small-molecule probes of bacterial imaging. Nat Chem Biol 12:472-8
Kocaoglu, Ozden; Tsui, Ho-Ching T; Winkler, Malcolm E et al. (2015) Profiling of ?-lactam selectivity for penicillin-binding proteins in Streptococcus pneumoniae D39. Antimicrob Agents Chemother 59:3548-55
Kocaoglu, Ozden; Carlson, Erin E (2015) Profiling of ?-lactam selectivity for penicillin-binding proteins in Escherichia coli strain DC2. Antimicrob Agents Chemother 59:2785-90
Wilke, Kaelyn E; Francis, Samson; Carlson, Erin E (2015) Inactivation of multiple bacterial histidine kinases by targeting the ATP-binding domain. ACS Chem Biol 10:328-35
Tsui, Ho-Ching T; Boersma, Michael J; Vella, Stephen A et al. (2014) Pbp2x localizes separately from Pbp2b and other peptidoglycan synthesis proteins during later stages of cell division of Streptococcus pneumoniae?D39. Mol Microbiol 94:21-40
Francis, Samson; Wilke, Kaelyn E; Brown, Douglas E et al. (2013) Mechanistic insight into inhibition of two-component system signaling. Medchemcomm 4:269-277
Wilke, Kaelyn E; Carlson, Erin E (2013) All signals lost. Sci Transl Med 5:203ps12

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