The proposed research will interrogate natural product scaffolds as starting points for antivirulence and narrow-spectrum agents. Of specific interest are compounds that mitigate bacterial biofilms, which are the causative agent in hospital-acquired infections, the development of resistance in bacteria, the rejection of medical implants, and many other health related diseases. The compounds, which this proposal will focus on, have been chosen from privileged areas where bacteria utilize chemical warfare to prevent colonization of invading species. Here we present a multi-faceted approach, including organic synthesis, molecular genetics, proteomics, transcriptomics, and microbiological assays that begins with these privileged scaffolds but has as an overarching goal of developing next generation therapeutics and tool compounds to better understand processes within a multispecies environment. The first two research thrusts seek to identify antivirulence compounds that inhibit one of the following processes: biofilm formation, quorum sensing, production of virulence factors, etc. Starting with known antifoulant and signaling molecules, we will explore the unique chemical features that endow each molecule with their biological effect. Furthermore, we will utilize the chemical toolbox to design compounds with improved chemical and physical properties to improve the likelihood of translation. Analogs will then be tested with the goal of identifying specific processes that the natural product affects and allow for a broader evaluation of the target in general biofilm processes. The third research thrust involves the chemical synthesis of natural product scaffolds identified in the rhizosphere. We have recently shown that these compounds possess species-specific activity, which is ideal for the development of ?narrow-spectrum? therapeutics and tool compounds. Proposed compounds are derived from plant material, endophytic fungi, and rhizosphere bacteria and have previously demonstrated biological activity. Central to the efficient and concise strategies proposed is the knowledge gained in our previously described total syntheses which provides key intermediates for analog development. The final thrust will investigate both the biological target and properties of the tool compounds both in single species and multispecies biofilms. This approach will employ a combination of genetic and MS-proteomic techniques to develop a candidate list of proteins, from which we will identify the targets by biochemical studies. Previous research has demonstrated that these sources have provided compounds with unprecedented biological activity with significant implications to improving human health. Furthermore, they act on therapeutic targets that were previously unknown providing new approaches to combat bacteria.

Public Health Relevance

This project utilizes synthetic chemistry, microbiology, genetics, and proteomic methods to develop novel compounds to combat bacterial biofilms, which are the causative agent in hospital acquired infections, the development of resistance in bacteria, the rejection of medical implants, and many other health related diseases. This research will develop antivirulence and species-specific tool compounds as potential therapeutic agents that perturb biofilm processes within pathogenic bacteria. The compounds are derived from natural product scaffolds isolated from regions rich in chemical diversity and bioactivity, which will undoubtedly shed light on the chemical underpinnings of these complex multispecies biofilm communities.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Unknown (R35)
Project #
7R35GM119426-02
Application #
9478451
Study Section
Special Emphasis Panel (ZRG1-CB-B (50)R)
Program Officer
Fabian, Miles
Project Start
2016-06-30
Project End
2021-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
2
Fiscal Year
2017
Total Cost
$380,777
Indirect Cost
$130,777
Name
Emory University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Steele, Andrew D; Ernouf, Guillaume; Lee, Young Eun et al. (2018) Diverted Total Synthesis of the Baulamycins and Analogues Reveals an Alternate Mechanism of Action. Org Lett 20:1126-1129
Keohane, Colleen E; Steele, Andrew D; Fetzer, Christian et al. (2018) Promysalin Elicits Species-Selective Inhibition of Pseudomonas aeruginosa by Targeting Succinate Dehydrogenase. J Am Chem Soc 140:1774-1782
Kim, Wooseong; Zhu, Wenpeng; Hendricks, Gabriel Lambert et al. (2018) A new class of synthetic retinoid antibiotics effective against bacterial persisters. Nature 556:103-107
Rossiter, Sean E; Wuest, William M (2017) EroS Enzyme from Aliivibrio fischeri Plays Cupid to Choanoflagellates. Chembiochem 18:2298-2300
Fletcher, M H; Burns-Lynch, C E; Knouse, K W et al. (2017) A novel application of the Staudinger ligation to access neutral cyclic di-nucleotide analog precursors via a divergent method. RSC Adv 7:29835-29838
Rossiter, Sean E; Fletcher, Madison H; Wuest, William M (2017) Natural Products as Platforms To Overcome Antibiotic Resistance. Chem Rev 117:12415-12474
Schallenhammer, Stephanie A; Duggan, Stephanie M; Morrison, Kelly R et al. (2017) Hybrid BisQACs: Potent Biscationic Quaternary Ammonium Compounds Merging the Structures of Two Commercial Antiseptics. ChemMedChem 12:1931-1934
Jennings, Megan C; Forman, Megan E; Duggan, Stephanie M et al. (2017) Efflux Pumps Might Not Be the Major Drivers of QAC Resistance in Methicillin-Resistant Staphylococcus aureus. Chembiochem 18:1573-1577
Steele, Andrew D; Keohane, Colleen E; Knouse, Kyle W et al. (2016) Diverted Total Synthesis of Promysalin Analogs Demonstrates That an Iron-Binding Motif Is Responsible for Its Narrow-Spectrum Antibacterial Activity. J Am Chem Soc 138:5833-6