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The Changing Face of Chemotherapy Postgrad Med J: first published as 10.1136/pgmj.64.753.552 on 1 July 1988. Downloaded from Postgraduate Medical Journal (1988) 64: 552-558 The changing face of chemotherapy W. Brumfitt and J.M.T. Hamilton-Miller Department of Medical Microbiology, The Royal Free Hospital School of Medicine, Pond Street, Hampstead, London NW3 2QG, UK. Summary: The historical development of antibiotics has been summarized. Three distinct phases are discernible. The first (from historical times to about 1900) involved mostly folk remedies. The second (1900-c. 1940) was ushered in by Paul Ehrlich's development of the concept of 'selective toxicity' and saw the establishment of arsenicals and sulphonamides. The third, lasting to the present day, started with the exploitation of the pioneering studies of Fleming, Dubos and Waksman on antibiotic production by soil fungi. This latest phase has continued with the improvement of natural products by the skills of the medicinal chemist. The properties and evolution of three major groups of antibiotics, penicillins, cephalosporins and aminoglycosides are fully described. Finally, pathways of possible future evolution of antibiotics are outlined. Introduction: from pre-history to the 20th century The idea of using natural or artificial substances to benedictur (the holy thistle) cures 'quartan agues', prevent or reverse 'putrefaction of wounds' is a and lovage 'resisteth poison and infection'. copyright. A very old one, and has been known since the start of modern herbal also gives many plant remedies - history. Thus, the ancient Egyptians used myrrh for example an extract of the coneflower (Echinacea (from Commiphora spp.) and frankincense (from sp.) is a specific for abscesses. It is interesting to Boswellia spp.), the Assyrians anticipated Paul note that such extracts have been shown to Ehrlich by several centuries by introducing arsenic. antagonize hyaluronidase. Also, at least one major The use of mercury, pioneered by the Arabs for pharmaceutical company is exploring the flora syphilis and championed by Paracelsus, lasted from found in Madagascar for pharmacological activity the 16th to the early 20th century. Moses was (including antimicrobial properties). advised to treat leprosy with hyssop (Leviticus, Before the germ theory had been properly http://pmj.bmj.com/ Ch. 14) and the Good Samaritan disinfected the formulated it had been realised intuitively for wounds of his assaulted fellow traveller by pouring centuries that many diseases were passed from in oil and wine (Luke, Ch. 11). The Romans person to person and that this chain could be dressed wounds with spider's webs dipped in honey broken by the use of appropriate chemicals. Thus, and also observed that keeping drinking water in simple antiseptics such as 'hydrated lime' (hypo- silver vessels prevented the spread of dysentery chlorite), tincture of iodine and phenol were in wide through their troops. Finally, mouldy bread often use by the mid-19th century. yields a growth of Penicillium spp. Thus it could be Ehrlich can justly be called 'The Father of on October 2, 2021 by guest. Protected speculated that the practice of applying mouldy Chemotherapy', and his researches on vital dyes bread to wounds was effective by virtue of such as methylene blue and trypan red and then antibiotic production. with arsenicals prepared the way for the antibiotic Plants were a rich source of antimicrobial era which was formally ushered in by Domagk and substances. Beside the examples already mentioned, his colleagues with the discovery that Prontosil cinchona bark was first used in Peru to combat rubrum had antibacterial properties in vivo. malaria, and ipecacuanha was found to be effective for amoebic dysentery. The famous British herbalist Synthetic compounds: the 1930s, the dawn of Culpepper (1826) lists many plants which are active rational chemotherapy in infections - to mention just two: Carduus Antifolate agents Correspondence: Professor W. Brumfitt, M.D., Ph.D., F.R.C.P., F.R.C.Path. The chemotherapeutic era, as generally recognized, ©) The Fellowship of Postgraduate Medicine, 1988 Postgrad Med J: first published as 10.1136/pgmj.64.753.552 on 1 July 1988. Downloaded from THE CHANGING FACE OF CHEMOTHERAPY 553 can be said to have started with the introduction of folate biosynthesis, arose from an area of research the sulphonamides into clinical use in 1935. These entirely different from that which involved the were outstandingly successful at first in the treat- sulphonamides. Both were found incidentally ment of meningitis, streptococcal infections and during the research programme by Burroughs infections of the urinary tract. Staphylococcal Wellcome into anti-cancer agents which would act infections, however, were found to respond rather by inhibiting human folate metabolism. Tri- poorly, due to the neutralization of the antibacterial methoprim is a remarkable compound in two activity of the sulphonamides by pus (see below). respects. First, it has a unique mode of action The active principle of Prontosil rubrum was amongst the antimicrobial agents by inhibiting an found to be sulphanilamide. Due to its relatively enzyme (dihydrofolate reductase) present in both low intrinsic antimicrobial activity (some 40 times bacterial and human cells. Second, the differential less than moder sulphonamides), large doses of toxicity between human and bacterial cells is this compound had to be used, with undesirable explained by small chemical differences in the struc- side effects. This provided a stimulus for chemists ture of human and bacterial dihydrofolate reductase to try to improve upon the existing molecule. These so that the affinity of trimethoprim is about 60,000 endeavours were successful in a remarkably short times greater for the bacterial enzyme. Thus, tri- time, maximally active sulphonamides such as methoprim in therapeutic doses has negligible sulphadiazine and sulphathiazole having been toxicity for host cells. Trimethoprim has enjoyed patented by 1942. This speed was due to the fact very wide usage worldwide in combination with that it had been shown that the antimicrobial sulphamethoxazole as co-trimoxazole (Septrin and activity of a sulphonamide depended upon its Bactrim). However, there is now no doubt that the ionization characteristics. This allowed rational syn- great antibacterial activity and wide therapeutic thetic programmes to be undertaken. Although the success of co-trimoxazole is due almost entirely to intrinsic activity of sulphadiazine could not be the trimethoprim component. Further, many of the improved upon, further modifications in the arguments in favour of the fixed combination, molecule have resulted in forward in are sulphonamide pharmaco- although probably put good faith, copyright. kinetically superior compounds such as sulfameto- specious. In particular the claims for synergy by pyrazine. The latter has a half-life of about 100 combining sulphonamide and trimethoprim and hours and can, therefore, be given once a week. also prevention of resistance to trimethoprim by the In this way were born the discipline of medicinal combination have not withstood scientific investi- chemistry and the concept of quantitative structure- gation. Unhappily, trimethoprim is an example of activity relationships (QSAR), both of which have an excellent drug the value of which has now played and will continue to play an enormously become eroded by increasing resistance. This is not important role in the development of improved only widespread in hospitals where resistance was antibiotics. due to an R factor but has subsequently spread http://pmj.bmj.com/ Sulphonamides were shown to exert their anti- into the community. To make matters worse bacterial activity by inhibiting the biosynthesis of because of integration of the R factor into the bacterial folate. Acquired resistance to these com- bacterial chromosome a stable resistance results. In pounds, which started to emerge soon after their the United Kingdom resistance includes strains of introduction, was due to alteration in the target Staphylococcus aureus especially those resistant to enzyme. The bacteriostatic action of sulphonamides methicillin (MRSA). The latter organisms are is reversed in the presence of substances such as p- proving to be a major therapeutic problem since so aminobenzoate and thymidine, which may be found few antibiotics are active against them. on October 2, 2021 by guest. Protected in pus. Research into sulphonamides also produced the anti-leprosy drug diaminodiphenyl sulphone Other synthetic compounds (Dapsone). Sulphonamide fell increasingly out of favour It is clear from the above that antimicrobial chemo- from the-late 1940s, due to increasing resistance therapy started by the exploitation of synthetic problems and the availability of broader spectrum molecules. It is notable, however, that following the antibiotics. arsenicals and anti-folate compounds, future advances in general mainstream chemotherapy have been made almost exclusively through natural pro- Other synthetic anti-folate antimicrobial compounds ducts and their chemical modification. On the other hand, some notable contributions have been made The anti-malarial pyrimethamine and the anti- in specific areas of chemotherapy by totally syn- bacterial trimethoprim, both inhibitors of microbial thetic compounds. These include the treatment of Postgrad Med J: first published as 10.1136/pgmj.64.753.552 on 1 July 1988. Downloaded from 554 W. BRUMFITT & J.M.T. HAMILTON-MILLER tuberculosis where
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