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Antibacterial Natural Products in Medicinal Chemistry-Exodus Or Reviews D. Häbich et al. DOI: 10.1002/anie.200600350 Antibiotics Antibacterial Natural Products in Medicinal Chemis- try—Exodus or Revival? Franz von Nussbaum, Michael Brands, Berthold Hinzen, Stefan Weigand, and Dieter Häbich* Keywords: Dedicated to Professor Robert E. Ireland antibiotics · genomics · glycopeptides · natural products · total synthesis Angewandte Chemie 5072 www.angewandte.org 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2006, 45, 5072 – 5129 Angewandte Antibiotics Chemie To create a drug, natures blueprints often have to be From the Contents improved through semisynthesis or total synthesis (chemical postevolution). Selected contributions from industrial and 1. Introduction 5073 academic groups highlight the arduous but rewarding path 2. Scope and Focus of this Article 5076 from natural products to drugs. Principle modification types for natural products are discussed herein, such as decoration, 3. Novel, Effective, and Safe Antibiotics are substitution, and degradation. The biological, chemical, and Urgently Needed 5077 socioeconomic environments of antibacterial research are 4. Antibacterials, an Arduous Marketplace 5078 dealt with in context. Natural products, many from soil organisms, have provided the majority of lead structures for 5. Biological Targets and Chemical Leads 5079 marketed anti-infectives. Surprisingly, numerous “old” classes of antibacterial natural products have never been intensively 6. Chemical Postevolution of Antibacterial Natural Products 5084 explored by medicinal chemists. Nevertheless, research on antibacterial natural products is flagging. Apparently, the “old 7. b-Lactam Antibiotics 5090 fashioned” natural products no longer fit into modern drug discovery. The handling of natural products is cumbersome, 8. Macrolide and Ketolide Antibiotics 5094 requiring nonstandardized workflows and extended timelines. 9. Lincosamides 5096 Revisiting natural products with modern chemistry and target- finding tools from biology (reversed genomics) is one option 10. Furanomycin, a Lead with Insufficient for their revival. Potential 5099 11. Pyrrolidinedione Antibacterials 5100 1. Introduction 12. Tetrahydropyrimidinone Antibiotics 5102 All industrialized societies rely on the pharmaceutical 13. Biphenomycins 5106 industrys ability to address their inherent medical needs. With infectious diseases, this trust is nourished by the ready 14. Tuberactinomycins and Capreomycins 5108 supply of a plethora of marketed antibiotics for the immediate 15. Glycopeptide Antibiotics 5110 16. Lysobactins 5114 17. Enopeptin Depsipeptide Antibiotics 5116 18. Summary and Conclusion 5118 19. Abbreviations 5119 treatment of routine or life-threatening bacterial infections.[1] Indeed, the research and development of antibacterial agents during the last century has been a chronicle of success, whereby all parties thrived. Since the introduction of the first sulfonamides and penicillins in 1935 and 1940 (Figure 1), the Figure 1. a) Nobel laureate, pioneer of antibacterial therapy, and inven- once marked mortality rate associated with bacterial infec- tor of the sulfonamides, Gerhard Domagk (1895–1964), with his most important working tool. Under the microscope he studied the effect of different chemicals on bacteria. b) Page from Domagk’s laboratory notebook describing the exceptional activity of azo dye D 4145 on [*] Dr. F. von Nussbaum, Dr. M. Brands, Dr. B. Hinzen, Dr. S. Weigand, streptococci. D 4145, launched in 1935 as “prontosil”, was a diazo Dr. D. Häbich prodrug of the active component 4-aminophenylsulfonamide that was Bayer HealthCare AG marketed in 1936 under the name “prontalbin”. At the outset, Medicinal Chemistry Europe antibacterial chemotherapy stemmed from synthetic dyes rather than 42096 Wuppertal (Germany) natural products. Essential principles of chemotherapy have been Fax : (+49)202-36-5461 worked out with the sulfonamides. E-mail: [email protected] Angew. Chem. Int. Ed. 2006, 45, 5072 – 5129 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 5073 Reviews D. Häbich et al. tions experienced a remarkable downturn.[2] Antibiotics[3] antibacterial research were the consequences of that falla- have saved millions of lives and eased patients suffering. cious consensus. After an innovation gap of several decades, Many of the antibacterial agents were natural products or an oxazolidinone (linezolid)[9] and a lipopeptide (daptomy- potent semisynthetic variations thereof (Table 1).[4–7] cin)[10, 11] were the first truly new chemical entities (NCEs) to Improved subclasses followed, such as the cephalosporins be launched. and carbapenems or, recently, the ketolides and glycylcy- Today, infectious diseases are the second major cause of clines. As a whole, they have served as structural scaffolds for death worldwide and the third leading cause of death in extensive medicinal-chemistry programs in virtually every developed countries (Table 2).[12] In the US, bacteria are the major pharmaceutical company. most common cause of infection-related death.[13] Antibiotics By the early 1970s, the existing therapies were seen as are no longer effective in all cases, and treatment options for adequate and the need for new antibiotics began to be certain microorganisms have become increasingly scarce.[14] questioned.[8] Waning public interest and health measures as Former last-resort drugs have become the first-line therapy. well as—with a time lag—declining industrial support for “Resistance threatens to turn back the clock” and is rapidly Franz von Nussbaum, born in Frankfurt/Main, studied chemistry at the University of Munich, where he received his PhD in the research group of Prof. W. Steglich (1998). After a postdoctoral Feodor-Lynen fellowship with Prof. S. D. Danishefsky at Columbia University (1999–2000), he joined Central Research at Bayer AG, Leverkusen. Since 2002 he has been working as a medicinal chemist for Bayer HealthCare AG in Wuppertal. The optimization of bioactive natural products is a central theme of his research interest. Michael Brands, born in Duisburg in 1966, studied chemistry at the Universities of Münster and Bochum/MPI für Kohlenforschung, where he received his PhD in 1993 in the group of Prof. H. Butenschön. After a postdoctoral stay in the group of Prof. W. Oppolzer at the University of Geneva (1993–1995), he joined the pharmaceutical division of Bayer AG as a medicinal chemist. Since April 2006 he has been a Director of Medicinal Chemistry, responsible for the chemical drug- discovery activities in the therapeutic areas of diabetes and heart failure. Berthold Hinzen was born in Cologne, Germany, in 1967. He studied Chemistry in Basel and obtained his PhD with Prof. F. Diederich at the ETH in Zürich, Switzerland (1996). After a postdoctoral fellowship in Prof. Steven Ley’s group in Cambridge, UK, he joined Bayer AG in Wuppertal in 1998 as a medicinal chemist. Since 2004 he has been a Director of Medicinal Chemistry, responsible for the chemical drug-discovery activities in the therapeutic area thrombosis. Stefan Weigand, born in 1969, studied chemistry at the Universities of Würzburg and Göttingen, where he received his PhD in 1997 in the group of Prof. R. Brückner. After a postdoctoral Feodor-Lynen fellowship under the guidance of Prof. B. M. Trost at Stanford University (1997–1998), he joined the pharmaceutical division of Bayer AG as a medicinal chemist. Since May 2005 he has been working as a group leader in cancer research at Roche Diagnostics GmbH in Penzberg. Dieter Häbich, born in Stuttgart, studied chemistry at the University of Stuttgart, where he received his PhD in the group of Prof. F. X. Effenberger in 1977. After a postdoctoral NATO-research fellowship with Prof. R. E. Ireland at California Institute of Technology in Pasadena, USA (1979–1980), he joined Bayer AG, Wuppertal as a medicinal chemist. In 1991 he became a Director of Medicinal Chemistry and has been responsible for chemical anti-infective research in the areas of antibacterials, antimycotics, and antivirals. 5074 www.angewandte.org 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2006, 45, 5072 – 5129 Angewandte Antibiotics Chemie Table 1: Introduction of new antibacterial classes for human therapy. Year Class Target Example Structure 1935 sulfonamides (synthetic) folate pathway prontosil 1 1940 b-lactams cell wall penicillin G 2 protein 1949 polyketides tetracycline biosynthesis 3 protein 1949 phenylpropanoids chloramphenicol biosynthesis 4 protein 1950 aminoglycosides tobramycin biosynthesis 5 protein 1952 macrolides erythromycin A biosynthesis 6 1958 glycopeptides cell wall vancomycin 7 DNA 1962 quinolones (synthetic) ciprofloxacin replication 8 Angew. Chem. Int. Ed. 2006, 45, 5072 – 5129 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.angewandte.org 5075 Reviews D. Häbich et al. Table 1: (Continued) Year Class Target Example Structure protein pristinamycin 1962 streptogramins biosynthesis (IA + IIA) 910 … protein 2000 oxazolidinones (synthetic) linezolid biosynthesis 11 bacterial 2003 lipopeptides daptomycin membrane 12 spreading, particularly in hospitals, where antibiotics are standards are thought to be in danger, in particular with heavily used.[15] The ability of bacteria to evade any form of regard to the antibacterial field.[19] The dilapidation of established therapy has become apparent and pathogens antibacterial drug discovery and development in combination resistant to one or more antibiotics are emerging and with a growing proportion
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