Topic:
Find a Needle in a Haystack  - Discovery of Platensimycin - A selective FabF Inhibitor With Potent in Vivo Antibiotic Properties

Abstract:
Bacterial infection remains a serious threat to human lives because of emerging resistance to existing antibiotics. Although the scientific community has avidly pursued the discovery of new antibiotics that interact with new targets, these efforts have met with limited success since the early 1960s.

Bacterial type II fatty acid synthesis (FASII) is an attractive target for antibacterial drug discovery because it is both essential for bacterial viability as well as significantly different from the corresponding human process in both organization and structure. ?-ketoacyl-(acyl-carrier-protein(ACP)) syntheses (FabH and FabF/B) are essential components of fatty acid biosynthesis and are highly conserved among key pathogens. Although no drugs targeting these enzymes are used in the clinic, cerulenin and thiolactomycin selectively inhibit FabF/B and FabH activities.  Several other inhibitors targeting these enzymes have been reported, but none are suitable drug candidates due to poor penetration, lack of target selectivity, and/or in vivo toxicity. We set up a new approach by combining antisense RNA (AS-RNA) technology with whole-cell screen techniques. We screened over 250,000 natural product extracts and discovered platensimycin, a previously unknown class of antibiotics produced by Streptomyces platensis. Platensimycin demonstrates strong, broad-spectrum Gram-positive antibacterial activity by selectively inhibiting cellular lipid biosynthesis. We show that this anti-bacterial effect is exerted through the selective targeting of FabF/B in the synthetic pathway of fatty acids. Direct binding assays show that platensimycin interacts specifically with the acyl-enzyme intermediate of the target protein, and X-ray crystallographic studies reveal that a specific conformational change that occurs on acylation must take place before the inhibitor can bind. Treatment with platensimycin eradicates Staphylococcus aureus infection in mice. Because of its unique mode of action, platensimycin shows no cross-resistance to other key antibiotic-resistant strains tested, including methicillin-resistant S. aureus, vancomycin-intermediate S. aureus and vancomycin-resistant enterococci. Platensimycin is the most potent inhibitor reported for the FabF/ B condensing enzymes, and is the only inhibitor of these targets that shows broad-spectrum activity, in vivo efficacy and no observed toxicity.

Brief Biography of the Speaker:
I got BS in biophysics (1982) from Fudan University (China) and received PhD in molecular biology and biochemistry (1994) from Kobe University (Japan). Post-doc training was in Dr. Elliott Ross' Laboratory in the Department of Pharmacology at UT Southwestern Medical center (Dallas). I served as an assistant professor in UT Southwestern Medical Center and University of Washington for 5 years. In 1999 I worked at a biotech company as a group leader on anticancer projects including NFkB and TGF? pathways, DNA array, phage display etc. Since 2000, I have been working at Merck & Co., Inc. as a senior biochemist, research fellow and project champion on food-animal growth promotion, infectious diseases and cardiovascular diseases. I have broad knowledge and extensive experience in biochemistry, enzymology, molecular biology, pharmacology, target validation, assay development and drug discovery. I also serve as reviewer for multiple Journals in above mentioned disciplines.  My research interests are 1) signal transduction and regulation of receptors (GPCR), G proteins, RGS proteins and protein kinases; 2) New target validation and drug discovery that includes bacterial cell division, cell wall and fatty acid biosyntheses, Mammalian fatty acid biosynthesis & oxidation, lipoprotein (LDL, HDL etc.) metabolism and peptide mimetics.

The recent references highly related to my presentation are listed below.

Singh SB, Jayasuriya H, Ondeyka J, Herath K, Zhang C, Zink DL, Tsou N, Basilio A, Genilloud O, Diez MT, Vicente F, Pelaez F, Young K and Wang J (2006) Isolation, Structure and Absolute Stereochemistry of Platensimycin, A Broad Spectrum Antibiotic Discovered Using an Antisense Differential Sensitivity Strategy, J. Am. Chem. Soc., 128 (36), 11916 -20

Wang J, Soisson SM, Young K, Shoop W, Kodali S, Galgoci A, Painter R, Parthasarathy G, Tang YS, Cummings R, Ha S, Dorso K, Motyl M, Jayasuriya H, Ondeyka J, Herath K, Zhang C, Hernandez L, Allocco J, Basilio A, Tormo JR, Genilloud O, Vicente F, Pelaez F, Colwell L, Lee SH, Michael B, Felcetto T, Gill C, Silver LL, Hermes JD, Bartizal K, Barrett J, Schmatz D, Becker JW, Cully D, Singh SB. (2006) Platensimycin is a selective FabF inhibitor with potent antibiotic properties, Nature, 441, 358-361

Young, K., Jayasuriya, H., Ondeyka, J.G., Herath, K., Zhang, C., Kodali, S., Galgoci, A., Painter, R., Brown-Driver, V., Yamamoto, R., Silver, L.L., Zheng, Y., Ventura, J.I., Sigmund, J., Ha, S., Basilio, A., Vicente, F., Tormo, J.R., Pelaez, F.,, Youngman. P., Cully, D., Barrett, J. F., Schmatz, D., Singh, S. B. and Wang, J. (2006) Discovery of FabH/FabF inhibitors from natural products, Antimicrob. Agents Chemother, 50 (2), 519-26

Kodali S, Galgoci A, Young K, Painter R, Silver LL, Herath KB, Singh SB, Cully D, Barrett JF, Schmatz D, Wang J (Jan 2005) Determination of selectivity and efficacy of fatty acid synthesis inhibitors., The Journal of Biological Chemistry, 280 (2), 1669-77

Seminar Series Coordinators:
Dr. Zeyuan Qiu    zeyuan.qiu@njit.edu      973-596-5357
Dr. Sergiu Gorun  gorun@njit.edu          973-596-6596