Syllabus Chemistry 259 Medicinal Chemistry of Modern Antibiotics Spring 2008 Instructor: Thomas Hermann, Pacific Hall 5222A, [email protected] Lecture Hours and Place: Tu/Th 5:00 – 6:20 pm, in Humanities & Social Sciences 1106B Office Hours: by appointment Web: http://tch.ucsd.edu/CHEM259.html Text: Antibiotics: Actions, Origins, Resistance, by C. Walsh, ASM Press Examination (for credits): Paper analysis & 20 min presentation Tentative Course Schedule: Lecture* Date Day Topic 1 April 1 Tu Introduction & Overview, Scope of the Course 2 April 3 Th History of Antibiotics 3 - 5 April 8 Tu I. Drug Discovery, Development & Approval Process Lecture 3: Drug Discovery Lecture 4: Preclinical and Clinical Development, Approval Lecture 5: Modern Target Discovery for Antibacterials and Mechanism of Action Studies (MOA) April 10 Th April 15 Tu April 17 Th 6 - 10 April 22 Tu II. Antibiotics Classes and Targets Lecture 6: Drugs Targeting Bacterial Cell Wall and Membrane Lecture 7: Drugs Targeting Fatty Acid and Folic Acid Biosynthesis, Cell Division Lecture 8: Drugs Targeting RNA and DNA Biosynthesis Lecture 9: Drugs Targeting Protein Biosynthesis; Introduction and 30S Subunit Target Lecture 10: Drugs Targeting Protein Biosynthesis; 50S Subunit and Other Targets April 24 Th April 29 Tu May 1 Th May 6 Tu May 8 Th May 13 Tu May 15 Th May 20 Tu III. Paper Presentations A list of suggested papers for presentation by the students is provided at the end of this syllabus. Presentations should be ~ 20 min, covering the subject of the paper plus, if necessary, describing some background information to explain the motivation for the published research. Presentations will be followed by questions & discussion. May 22 Th May 27 Tu May 29 Th June 3 Tu June 5 Th * Slides for the lectures can be downloaded in PDF format at the above web address. Some lectures/slide sets cover more than one lecture date.Chemistry 259: Medicinal Chemistry of Modern Antibiotics Spring 2008 11. Introduction & Overview; Scope of the Course The Special Topics Course will focus on the medicinal chemistry of modern antibiotics. We will discuss the discovery, mechanism of action, and synthesis of antibacterials that are currently being used in therapy. Emphasis will be given to compounds approved over the last three decades and investigational drugs that are in clinical trials. The process of antibacterial drug discovery and development will be outlined as an introduction. The optimization and preclinical development of antibiotics serve as transparent models to illustrate the integration of medicinal chemistry in the drug discovery process. ? >$800,000,000 10 - 15 years 051015202530198 9199 0199 1199 2199 3199 4199 5199 6199 7199 8199 9200 0Vancomycin-resistant enterococciChemistry 259: Medicinal Chemistry of Modern Antibiotics Spring 2008 2The Need for New Antibiotics: (Source: www.idsociety.org)Chemistry 259: Medicinal Chemistry of Modern Antibiotics Spring 2008 3References for Paper Presentations: (Select a paper from [1-25], or any other recent paper on a topic related to the course, and let TH know about your pick by beginning of May) 1. Akritopoulou-Zanze I, Phelan KM, Marron TG, Yong H, Ma Z, Stone GG, Daly MM, Hensey DM, Nilius AM, Djuric SW: Synthesis and antibacterial activity of novel bifunctional macrolides. Bioorg Med Chem Lett 2004, 14:3809-3813. 2. Angehrn P, Buchmann S, Funk C, Goetschi E, Gmuender H, Hebeisen P, Kostrewa D, Link H, Luebbers T, Masciadri R, et al.: New antibacterial agents derived from the DNA gyrase inhibitor cyclothialidine. J Med Chem 2004, 47:1487-1513. 3. Bastida A, Hidalgo A, Chiara JL, Torrado M, Corzana F, Perez-Canadillas JM, Groves P, Garcia-Junceda E, Gonzalez C, Jimenez-Barbero J, et al.: Exploring the use of conformationally locked aminoglycosides as a new strategy to overcome bacterial resistance. J Am Chem Soc 2006, 128:100-116. 4. Bronson JJ, DenBleyker KL, Falk PJ, Mate RA, Ho HT, Pucci MJ, Snyder LB: Discovery of the first antibacterial small molecule inhibitors of MurB. Bioorg Med Chem Lett 2003, 13:873-875. 5. Charest MG, Lerner CD, Brubaker JD, Siegel DR, Myers AG: A convergent enantioselective route to structurally diverse 6-deoxytetracycline antibiotics. Science 2005, 308:395-398. 6. Crowley BM, Boger DL: Total synthesis and evaluation of [Psi[CH2NH]Tpg4]vancomycin aglycon: reengineering vancomycin for dual D-Ala-D-Ala and D-Ala-D-Lac binding. J Am Chem Soc 2006, 128:2885-2892. 7. Disney MD, Seeberger PH: Aminoglycoside microarrays to explore interactions of antibiotics with RNAs and proteins. Chemistry 2004, 10:3308-3314. 8. Ferreras JA, Ryu JS, Di Lello F, Tan DS, Quadri LE: Small-molecule inhibition of siderophore biosynthesis in Mycobacterium tuberculosis and Yersinia pestis. Nat Chem Biol 2005, 1:29-32. 9. Hu X, Nguyen KT, Verlinde CL, Hol WG, Pei D: Structure-based design of a macrocyclic inhibitor for peptide deformylase. J Med Chem 2003, 46:3771-3774. 10. Huang Q, Kirikae F, Kirikae T, Pepe A, Amin A, Respicio L, Slayden RA, Tonge PJ, Ojima I: Targeting FtsZ for antituberculosis drug discovery: noncytotoxic taxanes as novel antituberculosis agents. J Med Chem 2006, 49:463-466. 11. Joseph-McCarthy D, Parris K, Huang A, Failli A, Quagliato D, Dushin EG, Novikova E, Severina E, Tuckman M, Petersen PJ, et al.: Use of structure-based drug design approaches to obtain novel anthranilic acid acyl carrier protein synthase inhibitors. J Med Chem 2005, 48:7960-7969. 12. Meroueh SO, Bencze KZ, Hesek D, Lee M, Fisher JF, Stemmler TL, Mobashery S: Three-dimensional structure of the bacterial cell wall peptidoglycan. Proc Natl Acad Sci U S A 2006, 103:4404-4409. 13. Mukhopadhyay J, Sineva E, Knight J, Levy RM, Ebright RH: Antibacterial peptide microcin J25 inhibits transcription by binding within and obstructing the RNA polymerase secondary channel. Mol Cell 2004, 14:739-751.Chemistry 259: Medicinal Chemistry of Modern Antibiotics Spring 2008 414. Nakama T, Nureki O, Yokoyama S: Structural basis for the recognition of isoleucyl-adenylate and an antibiotic, mupirocin, by isoleucyl-tRNA synthetase. J Biol Chem 2001, 276:47387-47393. 15. Nakayama K, Ishida Y, Ohtsuka M, Kawato H, Yoshida K, Yokomizo Y, Hosono S, Ohta T, Hoshino K, Ishida H, et al.: MexAB-OprM-specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 1: discovery and early strategies for lead optimization. Bioorg Med Chem Lett 2003,
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