The Chemistry of beta-Lactams

It is over sixty years since Alexander Fleming observed antibiosis between a Penicillium mould and bacterial cultures and gave the name penicillin to the active principle. Although it was proposed in 1943 that penicillin (1) contained a tJ-Iactam ring, this was not generally accepted until an X-ray crystallographic determination of the structure had been completed. RCONH )=r) o '" (I) 'C0 H 2 Penicillin was the first naturally occurring antibiotic to be characterised and used in clinical medicine. It is now seen as the progenitor of the tJ-Iactam family of antibiotics, which are characterised by the possession of the four membered tJ-Iactam ring. Chapters in this book will describe how current research has demonstrated that other lactam structures may also show antibacterial activity. Penicillins and cephalosporins (2), the second member of the tJ-Iactam antibiotic family, were both originally discovered in fungi but later detected in streptomycetes. Until 1970 penicillins and cephalosporins were the only examples of naturally occurring tJ-Iactam antibiotics. The discovery of 7-a-methoxy cephalosporins (3) from Streptomyces in 1971 stimulated the search for novel tJ-Iactam antibiotics from microbes, both by using sensitive new screening procedures, and by laboratory synthesis.

List of contents

1 The biosynthesis of ?-lactams.- 1.1 Introduction.- 1. 2 Penicillin and cephalosporin biosynthesis.- 1.3 Clavulanic acid biosynthesis.- 1.4 Carbapenem biosynthesis.- 1.5 Monocyclic ?-lactam biosynthesis.- References.- 2 Structure-activity relationships: chemical.- 2.1 The reactivity of the ?-lactam.- 2.2 Structural and ground-state effects.- 2.3 Kinetie effects.- 2.4 Summary of kinetic and ground-state effects.- 2.5 Structure-chemical reactivity relationships.- 2.6 Ease of C-N bond fission in ?-lactams.- References.- 3 Structure-activity relationships: biological.- 3.1 Introduction.- 3.2 General aspects.- 3.3 Natural penicillins.- 3.4 Penicillinase-resistant antistaphylococcal penicillins.- 3.5 Amino penicillins.- 3.6 Carboxy and sulfo penicillins.- 3.7 Acyl-ureido penicillins.- 3.8 Amidino penicillanic acid penicillins.- 3.9 6-?-Substituted penicillins.- 3.10 Cephalosporins.- 3.11 7-?-Acylamino group modifications.- 3.12 Substitutions on the 7-?-position.- 3.13 C-3 Substituent modifications.- 3.14 Orally adsorbed cephalosporins.- 3.15 Oxacephalosporins.- 3.16 Carbapenems.- 3.17 Penems.- 3.18 Monobactams.- 3.19 ?-Lactamase inhibitors.- 3.20 Conclusions.- References.- 4 The mechanisms of reactions of ?-lactams.- 4.1 Introduction.- 4.2 The aminolysis of ?-lactam antibiotics.- 4.3 Metal-ion catalysed hydrolysis.- 4.4 Micelle catalysed hydrolysis.- 4.5 The direction of nucleophilic attack.- 4.6 Thiazolidine ring opening.- References.- 5 Mode of action: interaction with the penicillin binding proteins.- 5.1 Introduction.- 5.2 Structure and biosynthesis of peptidoglycan.- 5.3 Penicillin-recognizing proteins as members of an 'active serine' enzyme family.- 5.4 Kinetics of the ?-lactam-PRP interaction.- 5.5 The physiological function of PBPs.- 5.6 PBPs involvedin resistance to ?-lactams.- 5.7 Site-directed mutagenesis results.- 5.8 Conclusions and perspectives.- Acknowledgements.- Dedication.- References.- 6 ?-Lactamase: mechanism of action.- 6.1 Introduction.- 6.2 Acyl-enzyme mechanism of ?-lactamase action: dass A ?-lactamases.- 6.3 The acyl-enzyme mechanism of ?-lactamase action: class C ?-lactamases.- 6.4 Metalloenzyme mechanism of ?-lactamase action.- Acknowledgements.- References.- 7 ?-Lactamase: inhibition.- 7.1 Introduction.- 7.2 ?-Lactamase and DD-peptidase active sites: structure and mechanism.- 7.3 Inhibitors of the serine ?-lactamase.- 7.4 Inhibitors of class B (metallo) ?-lactamases.- 7.5 Clinical indications.- 7.6 Retrospects and prospects.- References.- 8 Novel ?-lactam structures - the carbacephems.- 8.1 Introduction.- 8.2 Nomenclature.- 8.3 Synthesis.- 8.4 Stability of the carbacephs.- 8.5 Structure-activity relationships in the carbacephems.- Acknowledgements.- References.- 9 Non-?-lactam mimics of ?-lactam antibiotics.- 9.1 Introduction.- 9.2 Pyrazolidinones.- 9.3 Lactivicin.- 9.4 ?-Lactams.- 9.5 Imidazolidinones.- 9.6 Oxaziridines and epoxides.- 9.7 Cydobutanones.- 9.8 ?-Lactones.- 9.9 Summary.- References.- 10 Classical ?-lactam structures.- 10.1 Introduction.- 10.2 Sheehan's synthesis of penicillin V.- 10.3 Woodward's synthesis of cephalosporin C.- 10.4 Biomimetic synthesis.- 10.5 Merck synthesis of ( ± )-cephalothin.- 10.6 The Hoechst synthesis.- 10.7 Woodward's penem synthesis.- 10.8 The conversion of penicillins into cephalosporins.- 10.9 Cephamycin antibiotics.- 10.10 Merck synthesis of ( ± )-cefoxitin.- 10.11 Shionogi synthesis of a 7-?-methoxy-1-oxacephem.- 10.12 1 ,1-Dioxo-trans-7-methoxycephalosporanic acid t-butyl ester.- References.- Further reading.

Product details

• Assisted by: I Page (Editor), M I Page (Editor), M. I. Page (Editor), M.I. Page (Editor)
• Publisher: Springer Netherlands
• Languages: English
• Product format: Paperback / Softback
• Released: 11.03.2013
• EAN: 9789401053006
• ISBN: 978-94-0-105300-6
• No. of pages: 351
• Dimensions: 155 mm x 20 mm x 235 mm
• Weight: 569 g
• Illustrations: XIX, 351 p.
• Subject: Natural sciences, medicine, IT, technology > Chemistry > Organic chemistry