This application described experiments that will shed light on the bacterial cell cycle and elucidate ways in which this process might be targeted by small molecules to cure infections resistant to current antibiotics. Central to bacterial cell cycle is a protein called FtsZ, which is similar in structure to mammalian tubulin. Although many natural products and other small molecules target tubulin effectively, resulting in therapies for curing cancer, the ability to target the bacterial cell cycle and halt resistant infections has not been fully explored. We will develop efficient syntheses of several FtsZ-targeting natural products and we will use NMR spectroscopy to discern how these molecules interact with FtsZ. With this insight, we will then use computational chemistry to interpret the molecular interactions that result in binding and how to design more potent molecules. We will also use information provided by X-ray crystallography in the design of protein-mimicking small molecules that can disrupt bacterial cell division and possibly halt the bacterial response to DNA damage, which could render the organism more susceptible to current antibiotics.

Public Health Relevance

The proposed research will reveal new potential targets within that bacterial cell cycle that may enable new medicines to be developed to combat resistant infections. Many diseases caused by bacteria, such as "staph" infections caused by MRSA (methicillin-resistant Staphylococcus aureus), can no longer be cured with current antibiotics because the bacteria have developed resistance. Our research will result in knowledge about how bacteria divide and multiply so that this essential process, which may not mutate and develop resistance as quickly as other processes, can be targeted with new drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI080931-03
Application #
8277409
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Franceschi, Francois J
Project Start
2010-06-01
Project End
2015-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
3
Fiscal Year
2012
Total Cost
$367,091
Indirect Cost
$119,591
Name
University of California Davis
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Nepomuceno, Gabriella M; Chan, Katie M; Huynh, Valerie et al. (2015) Synthesis and Evaluation of Quinazolines as Inhibitors of the Bacterial Cell Division Protein FtsZ. ACS Med Chem Lett 6:308-12
Brockway, Anthony J; Grove, Charles I; Mahoney, Maximillian E et al. (2015) Synthesis of the diaryl ether cores common to chrysophaentins A, E and F. Tetrahedron Lett 56:3396-3401
Soldi, Cristian; Lamb, Kellan N; Squitieri, Richard A et al. (2014) Enantioselective intramolecular C-H insertion reactions of donor-donor metal carbenoids. J Am Chem Soc 136:15142-5
Arjes, Heidi A; Kriel, Allison; Sorto, Nohemy A et al. (2014) Failsafe mechanisms couple division and DNA replication in bacteria. Curr Biol 24:2149-55
Foss, Marie H; Eun, Ye-Jin; Grove, Charles I et al. (2013) Inhibitors of bacterial tubulin target bacterial membranes in vivo. Medchemcomm 4:112-119
Sorto, Nohemy A; Painter, Phillip P; Fettinger, James C et al. (2013) Design and synthesis of mimics of the T7-loop of FtsZ. Org Lett 15:2700-3
Moore, Jared T; Soldi, Cristian; Fettinger, James C et al. (2013) Catalytic Alkene Cyclization Reactions for the Stereoselective Synthesis of Complex "Terpenoid-like" Heterocycles. Chem Sci 4:292-296
Jimenez-Oses, Gonzalo; Brockway, Anthony J; Shaw, Jared T et al. (2013) Mechanism of alkoxy groups substitution by Grignard reagents on aromatic rings and experimental verification of theoretical predictions of anomalous reactions. J Am Chem Soc 135:6633-42
Anderson, David E; Kim, Michelle B; Moore, Jared T et al. (2012) Comparison of small molecule inhibitors of the bacterial cell division protein FtsZ and identification of a reliable cross-species inhibitor. ACS Chem Biol 7:1918-28
Grove, Charles I; Di Maso, Michael J; Jaipuri, Firoz A et al. (2012) Synthesis of 6,6'-binaphthopyran-2-one natural products: pigmentosin A, talaroderxines A and B. Org Lett 14:4338-41

Showing the most recent 10 out of 18 publications