147 Production and diversification of antibiotics 6.1 An introduction to antibiotics 148 6. 2 General strategies for the production of antibiotics 153 6.3 a brief history of penicillin production 6.4 Antibacterial mode of action of B-lactam antibiotics 6.5 Biosynthesis of penicillins and cephalosporins 6.6 Semi-synthetic penicillins 6.7 Cephalosporin diversification 6.8 Alternative strategies for product diversification 181 Summary and objectives Appendix 6.1 Examples of biotransformation of antibiotics(data abstracted from Sebek, O. K"Antibiotics"in Biotechnology Volume 6a, edited by Kieslich, K. 1984 Verlag Chemie, weihe
1 47 Production and diversification of antibiotics 6.1 An introduction to antibiotics 6.2 General strategies for the production of antibiotics 6.3 A brief history of peNcillin production 6.4 Antibacterial mode of action of fl-lactam antibiotics 6.5 Biosynthesis of penicillins and cephalosporins 6.6 Semi-synthetic penicillins 6.7 Cephalosporin diversification 6.8 Alternative strategies for product diversification Summary and objectives Appendix 6.1 Examples of biotransformation of antibiotics (data abstracted from Sebek, 0. K. "Antibiotics" in Biotechnology - Volume 6a, edited by Kieslich, K. 1984 Verlag Chemie, Weinheim). 148 153 156 164 165 168 179 181 186 187
hapter 6 Production and diversification of antibiotics 6.1 An introduction to antibiotics The discovery and production of antibiotics has been of tremendous importance to human and animal health care. Prior to their discovery about half a century ago, many bacterial infections caused debilitating diseases and fatalities were high. The discovery of antibiotics was a major step in the treatment of infectious diseases, especially those caused by bacteria. today about 50,000 tonnes of antibiotics are produced annually About a third of this consists of penicillins, whilst tetracyclines make up about a quarter of the market The first of the antibiotics that found practical use as a therapeutic was penicillin. The success of penicillin initiated a vast screening process all over the world, which resulted in the isolation of a large number of antibiotic substances from various natural sources. Many of these compounds were produced by micro-organisms and prove to be lethal for other micro-organisms. Many of these compounds were also very toxic to humans and could not be used therapeutically. Nevertheless a large number of classes of useful compounds were produced. The chemical structures of members of some of the most important classes are shown in Figure 6.1. ∏ Examine Figure 6.1 and see if you can identify the p-lactam structure in the first four structures shown B-lactam ring The structure you are looking for is a four membered ring containing three carbon atoms and a nitrogen atom in the ring. The structure you should have identified is You will see that this structure contains a tertiary amide You should examine the other structures shown, but we would not expect you to remember the details of these structures. You should, however be aware of the gene quinolones, tetracyclines, sulphonamides treptomycin
148 Chapter 6 Production and diversification of antibiotics 6.1 An introduction to antibiotics The discovery and production of antibiotics has been of tremendous importance to human and animal health care. Prior to their dimvery about half a century ago, many bacterial infections caused debilitating diseases and fatalities were high. The discovery of antibiotics was a major step in the treatment of infectious diseases, especially those caused by bacteria. Today about 50,OOO tonnes of antibiotics are produced annually. About a third of this consists of peNcillins, whilst tetracyclines make up about a quarter of the market. The first of the antibiotics that found practical use as a therapeutic was penicillin. The success of penicillin initiated a vast screening process all over the world, which resulted in the isolation of a large number of antibiotic substances from various ~Wal sources. Many of these compounds were produced by micro-organisms and prove to be lethal for other micro-organisms. Many of these compounds were also very toxic to humans and could not be used thempeutically. Nevertheless a large number of classes of useful compounds were produced. The chemical structures of members of some of the most impo+nt classes are shown in Figure 6.1. Examine Figure 6.1 and see if you can identify the f3-lactam structure in the first rI four structures shown. The structure you are loolung for is a four membered ring containing three carbon atoms and a nitrogen atom in the ring. The structure you should have identified is ptactamring You will see that this structure contains a tertiary amide. You should examine the other structures shown, but we would not expect you to remember the details of these structures. You should, however, be aware of the general forms of quinolones; tetracyclines; majordasses glycopeptides; of mlibiilics sulphonamides; aminoglycosides; macrolides; streptomycin
Production and diversification of antibiotics 14 lactam antibiotics (a monobactam (a ca non-B-lactam antibiotics )人 (a betraying Figure 6. 1 The chemical structure of some members of the important classes of antibiotics
Production and diversification of antibiotics 149 Figure 6.1 The chemical structure of some members of the important classes of antibiotics
150 Chapter 6 HoN HO HO chloramphenicol H2N H (a glycopeptide <>- 6N bactrim (a sulphonamide) (an aminoglycoside)Ho- NH erythromycin A (a macrolide Figure 6.1 Continued ∏ From these structures, would you expect each of these groups of antibiotics to act in the same way in target organisms
150 Chapter 6 Figure 6.1 _.______ Continued. n in the same way in target organism? From these structures, would you expect each of these pups of antibiotics to act
Production and diversification of antibiotics 151 modes of action You should have concluded that because these structures are very diverse, it is unlike that they will act in the same way. This is, in fact, true; the mode of action differs from one class of antibiotics to another We have listed some modes of action of antibiotics in Table 6.1 AntIbiotic Mode of actlon β Lactams Inhibition of synthesis of, or damage to, cell wall Penicillins Cephalosporins Monobactams Vancomycin Inhibitionof synthesis or metabolism of nucleic acids Polymyxins Inhibition of synthesis or damage to cytoplasmic membrane Polyene antifungals Sulfonamides Modification of energy metabolism Isoniazid Inhibition of protein biosynthesis Chloramphenicol Fusidic acid Table 6.1 Modes of action of antibiotics
Production and diversification of antibiotics 151 modes of adon You should have concluded that because these structures are very diverse, it is unlikely that they will act in the same way. This is, in fact, true; the mode of action differs from one class of antibiotics to another. We have listed some modes of action of antibiotics in Table 6.1. r\ntlbiotlc Mode of action &Lactams Penicillins Cephalosporins Monobactams Carbapenems dancomycin 3acitradn 3ycloserin zosfornycin 2uinolones Sifampin Uitrofurantoins Uitrolmidazoles Polymyxins Polyene antifungals Sulfonamides Trimethopim Dapsone Isoniazid Aminoglycosides Tetracyclines Chloramphenicol Erythromycin Clindamydn Spectinomycin Mupirocin Fusldk add Inhibition of synthesis of, or damage to, cell wall Inhibition of synthesis or metabolism of nucleic acids Inhibition of synthesis or damage to cytoplasmic membrane Modifition of energy metabolism Inhibition of protein biosynthesis Table 6.1 Modes of action of antibiotics