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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

W. Brumfitt and J.M.T. Hamilton-Miller Department of , The Royal Free Hospital School of Medicine, Pond Street, Hampstead, London NW3 2QG, UK.

Summary: The historical development of 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 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, , and 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 '. 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 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 such as 'hydrated lime' (hypo- silver vessels prevented the spread of dysentery chlorite), tincture of iodine and 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 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 - to mention just two: Carduus 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 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 especially those resistant to enzyme. The bacteriostatic action of sulphonamides (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 (). 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 where p-, , Gram-positive and Gram-negative pathogens, but , and are still resistance (generally caused by the spread of used. Other examples are the versatile nitro com- R-factor mediated fB-lactamases) emerged in Gram- pounds, of which , after 30 years, negative strains, particularly in the hospital remains invaluable in the treatment of urinary population, severely curtailing their usefulness. infections, the nitro- (, tini- Compounds such as and dazole) widely used both therapeutically and remain very useful today for most purposes in the prophylactically when anaerobes are pathogens, and domiciliary situation, and in hospitals flucloxacillin nitrothiazoles in schistosomiasis and other fluke remains effective for the majority of Gram-positive infestations. It is interesting to note that nitro- infections. However, the selection of bacterial resis- furantoin has a safety record which is better docu- tance continues relentlessly, and it is predictable mented than any other product used for the treat- that strains such as MRSA, JK diphtheroids and ment of urinary infections. enterococci will become more widespread (especially and the related 4-quinolones will in compromised patients), further reducing the be discussed in a later section. usefulness of penicillins. Even the recent develop- ment of inhibitors of fl-lactamases (such as and ) will probably only The 1940s: antibiotics from the soil partially alleviate this decline. is an example of a new class of Fleming's discovery of , reported in 1928, fl-lactam, namely the . This is an did not turn into a finding of clinical relevance example of a new antibiotic which is remarkable in until the mid-1940s, when the problems involved in having a range of activity restricted to the Gram- producing and purifying large amounts of the anti- negative organisms. Apart from its activity against biotic had been solved due to the efforts of Florey a number of important Gram-negative organisms and his colleagues, in collaboration with several the decreased likelihood of disturbing other pharmaceutical companies in the USA. However, commensal flora to be an may prove advantage. copyright. Fleming's observation stimulated others to search for antibiotics in soil organisms. Dubos discovered tyrothricin - a mixture of the peptide antibiotics The 1970s - the decade of the cephalosporins and tyrocidin (produced by Bacillus brevis) in 1939, and Waksman reported the The first commercially successful semisynthetic isolation of (from (cephalothin) was made in 1962, griseus) in 1944. While tyrothricin was too toxic for following the isolation of the 'nucleus' 7ACA from parenteral use, streptomycin revolutionized the cephalosporin C (this proved to be much more treatment of tuberculosis, and helped Waksman win difficult that the analogous process in the penicillin http://pmj.bmj.com/ the Nobel Prize. In the period between 1947 and series). However, for the first few years cephalo- 1957 (1947), (1947), sporins were perceived only as more expensive (1948), (1949), oxytetra- substitutes for penicillins. It was not until penicillin- cycline (1950), (1952), cephalosporin resistant bacterial strains became increasingly C (1955), (1956), (1956), common that the cephalosporins' intrinsic stability B (1957) and kanamycin (1957) - to to P-lactamases and the fact that this stability could name but a few - were reported. Some of these be increased greatly in a rational and predictable substances are still in use and will be referred to manner caused an increase in their use, especially in on October 2, 2021 by guest. Protected later. the treatment of nosocomial infections caused by Gram-negative . The advent of the so-called 'third generation' cephalosporins such as ceftazi- The 1960s - the decade of the penicillins dime which combine very high intrinsic activity, great fl-lactamase stability and activity against The isolation of the penicillin 'nucleus' (6APA) in must represent the peak of 1959 at Beecham Research Laboratories paved the achievement in this class of compound. These latest way for the semi-synthesis and marketing of a very cephalosporins seem set to replace aminoglycosides large number of penicillins. Some of the more as drugs of choice in the treatment of acute sepsis successful ones marketed in the 1960s have been: of unknown aetiology, and also seem likely to be ampicillin, amoxycillin, methicillin, flucloxacillin, effective alone in the primary treatment of infec- and , followed later by mezlo- tion, manifested by fever and leukopenia, in cillin, , and . These immunocompromised patients. It is interesting to compounds made a great impact initially on both note that the early cephalosporins ( Postgrad Med J: first published as 10.1136/pgmj.64.753.552 on 1 July 1988. Downloaded from THE CHANGING FACE OF CHEMOTHERAPY 555 and cephalothin) had a powerful action against medicinal chemist, was somewhat analogous to that Gram-positive bacteria but much less against which occurred in respect of the P-lactam anti- anaerobes, certain Gram-negative bacteria and biotics and the enzymes which inactivate them, the none against some important nosocomial strains, f-lactamases (see above). In the case of the amino- such as pseudomonads. By contrast, the latest com- glycosides the result of these collaborative efforts pounds (so-called third generation cephalosporins) included (a derivative of in are highly active against Gram-negative bacteria - which the inactivating enzymes' target sites were including the pseudomonads (especially Ps. aeru- protected). By contrast (a kanamycin B ginosa) and are also more active against anaerobes. product not available in the United Kingdom) is a However, this greater activity is gained at the product where the enzymes' targets have been expense of remarkably decreased activity against removed completely, thus solving the problem in a the Gram-positive bacteria. It is not widely different way. appreciated that no cephalosporin currently Amikacin has been in clinical use for some 12 available is active against Streptococcus faecalis. years, and resistance emergence so far has been Thus, superinfection with this organism is a well small. This may be because, due to its high cost, known complication of cephalosporin therapy. usage of amikacin has been relatively small. On the other hand, there is increasing published evidence that for this antibiotic resistance emergence may The aminoglycosides not be connected with total use. For whatever reason, amikacin can still be regarded as an anti- As mentioned above, streptomycin revolutionized biotic with a future, whereas the other amino- the treatment of tuberculosis in the 1950s, but the glycosides seem to be drugs the use of which is in ease with which bacteria acquired resistance and a decline. high propensity for ototoxicity and soon severely limited the use of this antibiotic for more use. too toxic for general Neomycin proved copyright. parenteral use, and kanamycin, although enjoying a Other groups of antibiotics which have benefited very wide market, never really became established from chemical modification as an of first choice due to its deficiencies against resistant hospital pathogens. The were isolated from Streptomyces The complex which was introduced in mediterranei but owe their current clinic therapeutic 1964, on the other hand, rapidly found favour for importance entirely to the skill of the medicinal the treatment of acute sepsis, due to its broad chemist. Of the original naturally occurring com- antibacterial spectrum. This included the much pounds rifamycin B had some antimicrobial activity feared pathogen Ps. aeruginosa which until then but this was insufficient for clinical use. The early http://pmj.bmj.com/ could only be treated by the polymyxins, the value modifications, rifamycin SV and rifamide, created of which was limited by their toxicity - especially little interest outside Italy, as they were of quite low nephro- and neurotoxicity. Early clinical use at too antibacterial activity, were somewhat erratically large a dose gave gentamicin the reputation of absorbed and had unfamiliar pharmacokinetic pro- being highly ototoxic and nephrotoxic, whereas files (due to being almost entirely in the when properly used - i.e. dosage controlled by bile). However, a later product, , has determining peak and trough levels in individual become extremely important in the treatment of patients - the incidence of toxicity is acceptably tuberculosis, and is increasingly being realised to be on October 2, 2021 by guest. Protected low. One problem about such monitoring is the an antibiotic of great potential for the management increased time and therefore cost which results of infections caused by MRSA and other recalci- from the need to obtain blood samples in order to trant Gram-positive species. carry out estimations at frequent intervals. is another natural product whose Increasing resistance among Gram-negative activity has been successfully increased by chemical bacilli during the 1970s led to intensive investi- means, in the form of . Lincomycin has gation of the cause of such resistance. The result of had a somewhat chequered history, having been these studies was the discovery of the large family introduced first as an antistaphylococcal agent. of aminoglycoside-inactivating enzymes. Once the Lincomycin and clindamycin enjoyed a resurgence biochemical mechanisms of action of these enzymes of popularity in the early 1970s due to their broad had been made clear it was possible to modify the anti-anaerobic spectrum as well as good activity antibiotic molecules to render them insusceptible to against Gram-positive cocci, but since that time enzymic attack. This process, involving close co- their association with antibiotic-induced colitis has operation between microbiologist, biochemist and reduced their usage substantially. Postgrad Med J: first published as 10.1136/pgmj.64.753.552 on 1 July 1988. Downloaded from 556 W. BRUMFITT & J.M.T. HAMILTON-MILLER

The are a large group of natural This group of compounds is very intrinsically active products of which only erythromycin and, to a against a wide range of Gram-negative rods much lesser extent, and (including Ps. aeruginosa), and have substantial have made any significant clinical impact in the activity against Gram-positive species as well. Long UK. has always been a problem half-lives mean that a twice daily schedule is with erythromycin, and chemical modifications - practicable. Their unique mode of action - on albeit of a relatively minor nature - have enabled DNA gyrase - suggests that resistance emergence this to be improved. Thus, the stearate and parti- may not be common. The quinolones are concen- cularly a recent development are trated in the tissues due to their lipophilicity, and better absorbed by mouth than the naturally so the only moderate blood levels that are attained occurring free base. Intramuscular (ethylsuccinate) must not be taken to imply (as would be the case and intravenous (lactobionate) preparations are for some other antibiotics) poor clinical also available. Another ester, the estolate, is now performance. Indeed, clinical trials in many indi- used with caution because of reports of hepato- cations show excellent results. It is too soon to be toxicity. It has apparently not been possible to alter dogmatic as to the place of the quinolones in the the antimicrobial spectrum of the macrolides by treatment of infectious diseases in general, but the chemical modification. These compounds are still first indications are certainly favourable, and have important, particularly in certain respiratory infec- done nothing to reduce the initial promise of these tions such as Legionnaires disease and mycoplasma drugs. A fuller assessment can be made in a few pneumonia. In campylobacter enteritis, erythro- years time. Meanwhile, we consider it important mycin is the drug of choice. For other indications that the quinolones be reserved for serious infec- are usually 'second line' antibiotics tions or the treatment of multi-resistant strains. It is but are often used as a substitute for to be hoped that use in general practice would be when the patient is 'penicillin sensitive'. severely curtailed - otherwise the problem of resis- In the series radical changes have tance may emerge. been made in both the antibacterial and pharmaco- copyright. kinetic properties. Beneficial characteristics have been introduced into this series by increasing the Drugs which have not been modified lipophilicity. and , which are semi-synthetic compounds, are the two best Included here are substances such as vancomycin examples: the former is active against many and . These are interesting in that the tetracycline-resistant staphylococci while the latter appearance of new problems, especially the MRSA, allows a once-a-day regimen due to its prolonged have resulted in these drugs being used much more half-life. commonly. In the glycopeptide field other drugs

In the past 5 years there has been a remarkable similar to vancomycin but apparently with better http://pmj.bmj.com/ change in the properties and chemotherapeutic pharmacokinetic properties and less toxicity have potential of the nalidixic acid group. The first appeared. Of these the one where investigation is clinically useful compound in this totally synthetic most advanced is . This should be avail- series, nalidixic acid, has been available since the able for general use by the summer of 1988. early 1960s. This was used purely as a urinary anti- infective. It has a spectrum limited to the common Gram-negative pathogens, and has to be given in a Examples of changes in the morbidity and mortality 6-hourly schedule in order to prevent resistance of infectious diseases unrelated to antimicrobial on October 2, 2021 by guest. Protected emerging. Early attempts to improve on these chemotherapy properties met with only modest success - , , and pipemidic While not underestimating the impact of anti- acid have been marketed but have found only a microbial agents on the control of infectious small therapeutic niche. However, a later phase of diseases remarkable changes which are unrelated to chemical modification in this series has had a these substances have been observed. The increasing spectacular result, as the fluorinated 4-quinolone availability of international statistics makes family has emerged. accurate analysis of these changes possible. The synthesis of these compounds probably Early in the 20th century tuberculosis was a represents the most exciting development in anti- universal scourge well deserving the epithet microbial chemotherapy since the isolation of bestowed upon it by Bunyan of the 'Captain of the 6APA. Already several have been marketed such as Men of Death'. However, a remarkable decline in , , , and the incidence of tuberculosis had already been and many more are under investigation. noted before the discovery of anti-tuberculosis Postgrad Med J: first published as 10.1136/pgmj.64.753.552 on 1 July 1988. Downloaded from THE CHANGING FACE OF CHEMOTHERAPY 557 drugs and, for that matter, before the discovery of Britain. Thus, as recently as 1942 recruiting to the the causal organism which was identified by Koch American Air Force was almost halted because of in 1882. epidemic streptococcal sore throat followed by an Subsequently important factors in the control of incidence of rheumatic fever which was as high as 4 the disease were improvement in housing, nutrition per cent. Only a decade later a number of reports and sanitation together with the knowledge that concerning patients with streptococcal sore throat tuberculosis was a transmissible disease. in the USA and in this country have shown an However, antibiotics played an important part in incidence of rheumatic fever of 0.1 per cent or less. the treatment of tuberculosis. The advent of anti- The reason for a change to the benign nature of tuberculosis drugs, notably streptomycin (1944), such infections remains unclear. However, circum- para-amino salicyclic acid (1946) and isoniazid stantial evidence strongly indicates that a decrease (1952) revolutionized the treatment of all forms of in the virulence of Group A f-haemolytic strepto- tuberculosis. From the patient's point of view the cocci for humans is an important factor. outlook of uncertainty, or of despair, was replaced The fall in incidence of rheumatic fever following by one of confident optimism. Long periods of bed infection by fl-haemolytic streptococcus Group A rest are now unnecessary and although appropriate has not been brought about by the availability of surgical treatment is of great importance in certain antibiotics. Although it was shown that by treating cases, it is true to say that efficient chemotherapy a streptococcal sore throat with a 10-day course of leaves only the occasional case where it is required. benzylpenicillin, which eliminates the streptococci, The discovery of new anti-tuberculosis agents rheumatic fever was prevented, it is now known especially those which are bactericidal and pene- that even in the absence of antibiotic treatment trate cells have resulted in advances in treatment. rheumatic fever rarely complicates streptococcal These include the reduction of duration of treat- pharyngitis. This is an example of change in the ment (which initially was two years and is now virulence of an organism which is unrelated to the three months), and oral treatment allowing therapy use of antibiotics. at home with obvious cost benefits. Problems still remain, for example non- copyright. compliance by patients may lead to the emergence Future prospects of resistant organisms. Also lack of awareness of the danger of tuberculosis led to a reduction in The last 50 years have seen a rapidly evolving BCG vaccination of 'at risk' subjects and picture in terms of available antibiotics, and many consequently of herd immunity. groups have experienced rises and falls. Examples Tuberculosis is an example of a serious infection of 'antibiotics of today' are fl-lactams (cephalo- where antimicrobial drugs only play a part in its sporins, , monobactams and ,f- control. However, a more striking example is the lactamase inhibitors), aminoglycosides, quinolones http://pmj.bmj.com/ global eradication of smallpox which has been and rifampicin. 'Antibiotics of yesterday' must achieved without the help of specific antiviral include streptomycin and sulphonamides. Of great agents. In contrast, an example of persistence of a interest is the question: which will be the 'anti- transmissible disease, in spite of the availability of biotics of tomorrow'? While one can only speculate etfective chemotherapeutic agents, is malaria. on this topic, there are several directions which can A change in virulence of an organism (as be seen as distinct possibilities for the future evo- opposed to host resistance) may also cause a lutionary pattern of antibiotic development. These decrease in morbidity and mortality in infectious include: on October 2, 2021 by guest. Protected disease. A remarkable example of this is rheumatic (a) The revival of 'old' antibiotics in response to fever: this is well known to be associated with new needs. We see definite prospects for the streptococcal sore throat which is therefore an renaissance of a compound related to novobiocin in essential precursor of the disease. However, response to the appearance of MRSA. The nitro- evidence from mortality rates and from necroscopy furans also have the advantage of very rare resis- studies on children leaves little doubt that in the tance acquisition. Nitrofurantoin is still valuable in economically developed countries of the temperate the treatment of urinary infections. zone, rheumatic fever in its more serious and easily (b) Renewed search for new natural products. It recognized forms has decreased progressively in had been thought that resources capable of pro- incidence since at least the beginning of the ducing new natural antibiotics were exhausted, twentieth century. This process of decline under- following the long phase of no further discoveries went acceleration after 1930 and has since con- after gentamicin. However, the finding of such tinued, but foci of higher incidence persist in compounds as the monobactams and teicoplanin certain urban areas of the United States and showed that this view was erroneous. Large poten- Postgrad Med J: first published as 10.1136/pgmj.64.753.552 on 1 July 1988. Downloaded from 558 W. BRUMFITT & J.M.T. HAMILTON-MILLER tial sources of new natural products remain rela- specific ultra-narrow antibacterial spectra should be tively untapped - e.g., the Plant Kingdom. developed to complement the existing very broad (c) Production of new chemical entities. To avoid spectrum compounds. The new class of antibiotics cross-resistance, it would seem logical to concen- would be used once the invading pathogen had trate on molecules whose chemical structure differs been accurately identified. There are already completely from those of existing antibiotics rather examples of narrow spectrum compounds in use, than to continue to modify existing molecules. notably against Ps. aeruginosa. Examples of this approach already exist, for It will be an instructive and perhaps humbling instance in paldimycin and the Du Pont series of exercise to re-read this article in the year 2000, and oxazolidinones. to see how many predictions have proved true. (d) The production of antibiotics with highly

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