Penicillin Chapter 13 1957 Be the Wrath of God, Punishing Man for His Sins

Home , Ernest Duchesne, Gerhard Domagk

Penicillin Chapter 13 1957 be the wrath of God, punishing man for his sins. Pasteur’s seminal works culminated in the ‘germ theory of disease,’ which asserted that infectious diseases were caused not by God’s vengeance, but by microbes. Louis Pasteur studied chemistry in he narrative surrounding 3DULVDQGLQKHPDGHKLV¿UVWSUR- found contribution to the advancement of the discovery and develop- science, aged just twenty-six. He exam- ment of penicillin is truly ined tartaric acid crystals under a micro- scope and noticed that they existed in two remarkable, possessing all distinct forms that were mirror images of the ingredients of a best-selling each other. He was able to separate these novel: serendipitous discovery, war- forms and discovered that, in solution, they rotated the plane of polarized light - WLPHSROLWLFDOLQWULJXH¿HUFHFRPSHWL in opposite directions. This investigation tion, and an eclectic cast of characters. represents the inception of the pivotal and In addition, the dreadful problem of IXQGDPHQWDO¿HOGRIVWHUHRFKHPLVWU\7KH tartaric acid Pasteur studied came from fatal bacterial infections was solved. wine sediments, and his interest in the sci- All this was a consequence of ence of fermentation would lead to more the extraction of a broad- important discoveries. In 1856, Pasteur came to the aid of a student’s family, who spectrum antibiotic from were experiencing production problems at Alexander Fleming in his laboratory an ordinary mold, follow- their fermentation plant; sometimes alco- hol was produced as expected, but other ing an observation made Pasteur’s philosophy on nature, batches gave lactic acid instead. Pasteur Box 1 by Alexander Fleming in examined the fermentation mixtures by research, and humanity 1928. Despite its impor- microscopy and noticed that during normal production the yeast cells were plump and tance and the efforts of budding, but when lactic acid was being many chemists, the total produced, the yeast cells were smaller ,EHVHHFK\RXWRWDNHLQWHUHVWLQWKHVH synthesis of penicillin would and accompanied by rod-like microbes. VDFUHGGRPDLQVVRH[SUHVVLYHO\FDOOHGODE +H IRXQG WKDW EULHÀ\ KHDWLQJ WKH OLTXLG not be accomplished until 1957. RUDWRULHV$VNWKDWWKHUHEHPRUHDQGWKDW medium before fermentation began would kill the undesirable microbes and lead to WKH\EHDGRUQHGIRUWKHVHDUHWKHWHPSOHV This epic story begins much earlier, reproducible fermentations. This steriliza- RIWKHIXWXUHZHDOWKDQGZHOOEHLQJ,W however, with a revolution in our under- tion procedure, known as pasteurization, LVKHUHWKDWKXPDQLW\ZLOOJURZVWUHQJWKHQ standing of the underlying cause of disease. is still in common use today, particularly DQGLPSURYH+HUHKXPDQLW\ZLOOOHDUQWR %HIRUH WKH PDJQL¿FHQW DFFRPSOLVKPHQWV for dairy products. Pasteur was subse- UHDG SURJUHVV DQG LQGLYLGXDO KDUPRQ\ LQ of Louis Pasteur, disease, death, and ill- quently able to show, using an ingeniously WKHZRUNVRI1DWXUHZKLOHKXPDQLW\ VRZQ ness were frequently ascribed metaphysi- GHVLJQHG VZDQQHFNHG ÀDVN FRQWDLQLQJ D cal causes. In the western world, this idea fermentable solution, that microbes such ZRUNV DUH DOO WRR RIWHQ WKRVH RI EDUED commonly meant that sickness, especially as these were airborne particles. Next, he ULVPIDQDWLFLVPDQGGHVWUXFWLRQ in the form of epidemics, was deemed to tackled a serious disease in silk-producing

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98 Penicillin worms whose malaise was having a dev- astating economic impact on the buoy- ant European silk trade. He showed that healthy worms could become infected by nesting on leaves previously occupied by GLVHDVHG VSHFLPHQV 7KHVH HDUO\ LQÀXHQ- tial studies led Pasteur to develop his idea that germs spread contagious diseases, was being used to treat sewage in Carlisle, and that these foreign particles were liv- DQG WKDW ¿HOGV WUHDWHG ZLWK WKH UHVXOWLQJ ing micro-organisms. Pasteur went on to slurry were freed of a contagion that would do more groundbreaking work. Building on normally lead to infection in cattle grazing Edward Jenner’s discovery of a vaccine for on the same site. Lister began to clean smallpox, Pasteur developed vaccination wounds and dressings with a carbolic acid as a prophylactic strategy to outwit other solution, and in 1867 he was in a position to viral contagions, such as rabies, as well announce to the British Medical Association as the bacterial infections of anthrax and that his ward had been sepsis-free for an cholera. Having sensed the widespread astonishing nine month period due to the recognition of his work, Pasteur died with implementation of this protocol. Lister the knowledge that he had succeeded had pioneered the use of antiseptic solu- in bequeathing France a powerful and tions and broadcast the importance of vibrant establishment for research, The hygiene in operating theatres, thereby Pasteur Institute, in Paris. He had pursued saving innumerable patients from a this project with passion for he strongly painful gangrenous death. believed in applying experimental science The German doctor Robert to eradicate humanity’s plagues and often Koch, working alone as the District Joseph Lister Robert Koch spoke emphatically on this subject (Box 1). 0HGLFDO 2I¿FHU IRU :ROOVWHLQ GXU- His words ring true and are surprisingly rel- LQJ WKH )UDQFR3UXVVLDQ :DU LQ evant even in today’s much altered world. WKHVZDV¿QDOO\DEOHWRVKRZ Joseph Lister, pioneer of antisepsis, Meanwhile, in the United Kingdom, GH¿QLWLYHO\WKDWWKHDQWKUD[EDFLOOXV attending to a patient a young Quaker surgeon by the name of directly causes disease in test ani- Joseph Lister was enthralled by Pasteur’s mals. He also developed techniques work, prompting him to propose a connec- for culturing bacteria, thereby illustrating Vi e tion between wound sepsis and microbes WKHSKHQRPHQDOUHVLOLHQFHRIWKHVHVSHFL¿F brio cholera from the air. Lister’s search for the cause microbes, while also proving that, in general, of sepsis had begun because he was a host animal was not necessary for these troubled by the assertion made earlier by germs to thrive. He photographed cultures, the famous chemist Justus von Liebig that studied the conditions required for bacterial sepsis was a kind of combustion occurring growth, and developed stains to improve when expanding moist body tissue met their visibility. It was by employing this with oxygen from the air. In Lister’s surgi- knowledge that he was able to identify both FDO ZDUG DW WKH *ODVJRZ 5R\DO ,Q¿UPDU\ the Vibrio cholerae and the Mycobacterium ZRXQG VHSVLV NLOOHG ¿IW\ SHUFHQW RI KLV tuberculosis that cause the deadly diseases patients. Lister was further inspired to do of cholera and tuberculosis, respectively, something about this dreadful situation work which earned him the 1905 Nobel when he read that carbolic acid (Box 2) Prize in Physiology or Medicine.

99 Chapter 13 IDVFLQDWHGE\ZKDWLQÀXHQFHGWKHGLVSDU- ity between various cell types. The large number of dyes produced by the German dye industry at the time afforded Ehrlich with a vast array of chemical candidates for testing. He and his Japanese colleague, Kiyoshi Shiga, eventually found Identifying these disease-causing that trypan red (an azo dye, Box 2) could agents had been a long and arduous effectively kill the bacteria Trypanosoma battle requiring all the energy of those gambiense, the causative agent of the distinguished scientists whose ingenious fatal sleeping sickness transmitted by the work had already revolutionized medical WVHWVH À\LQ$IULFD+RZHYHULQWHVWVRQ practice, as we have just seen. Each of humans in Uganda, its use resulted in these men left his own indelible mark on unacceptable side effects ranging from history, immediately contributing to saving blindness to death. Ehrlich is also famous lives, yet our story is just in its beginning. for introducing the arsenic salts salvarsan At the start of the twentieth century life (arsephenamine) and neosalvarsan (neo- H[SHFWDQF\LQ(QJODQGZDVMXVWIRUW\¿YH arsephenamine) as drugs to treat syphilis years, and infant mortality was at a rate (caused by Treponema pallidum infection). RIRQHKXQGUHGDQG¿IW\SHUWKRXVDQGOLYH Pain at the injection site, side effects, births. Many of the premature deaths that and frequent relapses rapidly consigned Paul Ehrlich Gerhard Domagk contributed to these appalling statistics these agents to history. Nevertheless, could be attributed to fatal bacterial infec- Ehrlich’s studies launched the age of che- WLRQV%DFWHULDKDGEHHQLGHQWL¿HGURXWHV motherapy. Ehrlich was also a pioneer in of transmission had been elucidated, and WKH¿HOGVRIKHPDWRORJ\DQGLPPXQRORJ\ Box 2 Pre-penicillin antibacterial agents sterilization and surgical hygiene to prevent with his contributions being recognized by infection had been proven, yet still no solu- the awarding of the 1908 Nobel Prize in tion to the problem of successfully treating Physiology or Medicine, which he shared an already-infected patient was available. with the Russian Ilya Ilyich Mechnikov, “in People had good reason to dread bacterial recognition of their work on immunity.” infections since they frequently ended with In 1927, Gerhard Domagk, while con- the death of their victim. tinuing investigations in the same vein at Paul Ehrlich, a friend and one-time the laboratories of I. G. Farbenindustrie, colleague of Koch, suggested that bacte- FRQFHQWUDWHG PDLQO\ RQ ¿QGLQJ DJHQWV rial infection might be curable by treat- effective against haemolytic Streptococci ment with a drug that was toxic (the bacteria associated with throat infec- towards the bacteria, whilst being tions). He recommended prontosil rubrum harmless to the patient, thus (Box 2), a red azo dye, for clinical trials – a introducing the so-called ‘magic fortunate choice, for this compound con- bullet’ concept. This idea had tains the critical sulfonamide functionality been inspired by the selective and proved to be very effective against uptake of dyes into bacterial WKHVHEDFWHULD6RLWZDVWKDWWKH¿UVWFOLQL- cells, a technique that had cally used sulfonamide antibacterial agent been developed for enhancing was born, to be followed soon by many microscopy, and Ehrlich was other members of this same class. The dis-

Petri dish 100 Penicillin covery of the antibacterial effects of prontosil won Gerhard Domagk the Nobel Prize in Physiology or Medicine in 1939. His real triumph, however, was much more personal, as it emerged later that Domagk had, in tion elsewhere. The desperation, used prontosil captain of St. Mary’s rubrum successfully to treat ULÀH FOXE ZKR UHOLHG his infant daughter, who was RQ )OHPLQJ¶V ÀDZOHVV F dying of Staphylococcal scep- le h shooting skills, heard of m is tacemia, long before the drug in i d his impending departure g’ tr became available to the public. After s famous pe and did his best to prevent it an initial period of euphoria over the discov- by winning him over to his own dis- ery of the sulfonamides the febrile activity cipline, bacteriology, thereby maintain- calmed and their shortcomings began to ing the integrity of his champion team. become all too apparent. Although still Alexander Fleming never left St. Mary’s, used in rare cases today, these antibacteri- becoming instead the world’s most famous als are very narrow in spectrum and essen- bacteriologist. tially obsolete. ,QWKHV)OHPLQJLGHQWL¿HGO\VR- Enter Sir Alexander Fleming, the son zyme, an enzyme found in tears, which Sir Alexander Fleming of a farmer from rural Scotland, whose exhibited a natural and mild antibacterial entire career could be said to have been DFWLRQ7KLVSURWHLQZDVWKH¿UVWDQWLELRWLF based on a series of serendipitous happen- to be isolated from the human body, but as Box 3 Highly contested structures of penicillin ings. In 1900, the young Alec, as he was it was not powerful enough to attack the called, joined a Scottish regiment in order most prevalent and aggressive infections, WR ¿JKW LQ WKH %RHU :DU ZLWK WZR RI KLV Fleming continued his search. One day, so brothers. This experience honed his swim- the legend goes, when he was clearing out ming and shooting skills, but never actually petri dishes containing bacterial cultures took him as far as the war-torn Transvaal that had begun to accumulate in one of his region of South Africa (a province lying sinks, he noticed that one of the containers between the Vaal and Limpopo rivers). On had a mold growing on the nutritional agar. returning to London, and in need of a pro- This rather common occurrence was made fession, Fleming decided to follow his older fascinating by the fact that Fleming’s habit brother into medicine. He obtained top of careful observation also revealed that no scores in the qualifying examinations, giv- bacterial colonies were growing around the ing him a free hand over which school he periphery of the fungus. Fleming went on might choose for his studies. He elected to to show that not only was bacterial growth enroll at St. Mary’s, one reason being that inhibited, but that healthy bacteria under- he had played water polo against them in a went cell lysis and death when exposed to SUHYLRXVVSRUWLQJ¿[WXUH,Q)OHPLQJ the mold (Penicillium notatum). It should found himself specializing in surgery, a be noted at this point that the full detailed career choice which would require him to tale of the discovery of penicillin has its leave St. Mary’s in order to take up a posi- roots earlier than Fleming’s investigations.

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101 Chapter 13 FDSWLYDWLQJLQWHUQDWLRQDOVFLHQWL¿FDGYHQ- tures, the so-called Penicillin Project. :LWK WKH RXWEUHDN RI :RUOG :DU ,, LQWHUHVW LQ SHQLFLOOLQ KDG LQWHQVL¿HG Numerous scientists strove to produce the antibiotic on a large scale in response to an urgent new need for the drug to treat Both Joseph Lister and Ernest Duchesne wounded soldiers and civilians who had (a French medical student) independently subsequently contracted infections. The reported the use of Penicillium molds proximity of the battle frontline, the fre- in bandages to treat infected patients quent aerial bombardments of the UK, and at the end of the nineteenth century. the need for a rapid solution to the prob- These compresses were ignored by lem led to a huge Anglo-American collabor- WKHVFLHQWL¿FDQGPHGLFDOFRPPXQLWLHV ative project on penicillin. The Rockefeller due to their low potency until Fleming Foundation in New York arranged for Florey rekindled interest in them. Furthermore, and Heatley to come to America in 1941 Chinese medical texts dating back some to meet with Charles Thom, chief mycolo- 3000 years advocated the use of moldy gist at the US Department of Agriculture. A soybean curd to treat skin infections. two-pronged strategy for the procurement At the beginning of the 1930s, and development of penicillin was imme- frustrated by progress in advancing his GLDWHO\IRUPXODWHG7KH¿UVWDSSURDFKZDV discovery to the next stage, Fleming directed towards the elucidation of the passed on some of his culture to Howard structure of penicillin, which would make Alexander Fleming and the Oxford penicillin team: :)ORUH\DQG(UQVW%&KDLQDW2[IRUG the ultimate goal of its chemical synthe- Fleming, Florey, Chain, Sanders, Abraham (left to right) University. The Oxford group, which also sis at least conceivable. Upwards of forty included Norman G. Heatley and Edward independent laboratories and hundreds 3$EUDKDPUH¿QHGWKHJURZWKDQGLVROD- of chemists became involved in this lab- Box 4 The mechanism of action of penicillin tion of the penicillin extracts just enough yrinthine task. The second line of attack to facilitate the instigation of clinical trials, was directed towards further improving which immediately began to deliver very the fermentation process for production promising results. However, pure penicil- of the drug. The latter of these pivotal lin was still in such short supply that it works was relocated to the US Agriculture had to be recovered from the urine of Department Laboratories in Peoria, Illinois. patients for reuse. The spectacular suc- Here an intense research program drew on cess of penicillin as an antibiotic would DP\ULDGRIVRXUFHVWR¿QGH[WUDPRPHQ- later earn Fleming, Chain, and Florey the tum; in this eclectic project, progress was 1945 Nobel Prize in Physiology or even aided by local residents who Medicine. In the meantime, brought moldy household the elevation of penicillin to items to the laboratories its legendary status as a for investigation in the world-changing antibi- search for more produc- otic would require the tive penicillium strains. launching and suc- It was the sec- cessful execution of ond of these two one of history’s most approaches that paid

P e n um ici n llium soge 102 chy Penicillin the earliest dividends. Thus, a much-improved yield of penicillin was secured in the 1940s from Penicillium chrys- ogenum, a discovery made courtesy of a moldy cantaloupe mankind. Overall, this melon brought into the venture succeeded R laboratory by Mary Hunt, i e admirably in optimizing p n an employee at the Peoria en vi fermentation and produc- in a ODERUDWRULHV :LWKLQ WKUHH g n tion protocols, allowing for a can pe o years, twenty-nine plants were fer- talou successful and practical supply menting this high-yielding fungal strain to of the new miracle drug, ultimately sav- produce penicillin using a corn-steep liq- ing countless lives. The process, how- uid medium (a by-product of the massive ever, still relied on natural biosynthesis 0LG:HVW FRUQ SURGXFWLRQ LQ DQ DPD]- of the intact penicillin molecule, a fact ing effort organized by an extraordinary that limited investigations into producing FRQJORPHUDWLRQ RI VFLHQWL¿F HVWDEOLVK- analogs with enhanced activity, especially ments. The pharmaceutical companies of to combat the new demon of bacterial 0HUFN3¿]HU6TXLEEDQG$EERWWZHUHDOO resistance that was just beginning to involved, along with leading British and rear its ugly head. These impera- American academic and governmental tives stipulated urgent attention institutions. EH SDLG WR ¿QGLQJ D FKHPLFDO General Dwight D. Eisenhower began synthesis. Dorothy Crowfoot Hodgkin and husband the invasion of Europe from the southern Before a chemical synthesis shores of England on D-Day supported by could be attempted the non- some three million doses of penicillin (300 trivial task of deconvoluting the General Dwight D. Eisenhower (left) confer- billion units or approximately 180 tonnes), molecular structure of penicil- ring with General Bernard Montgomery the product of one of the most exciting lin had to be accomplished. From and lucrative joint ventures in history. the ardent debate amongst many Only the notorious Manhattan Project of the most renowned chemists of the directed towards the development of the time, two possible structures emerged atom bomb exceeded it in magnitude in the early 1940s as leading contenders during that period. Thus, in less than four for the honor of representing the magical years, scientists had gone from recover- molecule of penicillin (see Box 3). The so- ing penicillin from patients’ urine, due to called oxazolone-thiazolidine formula was its short supply, to the phenomenal level proposed by Sir Robert Robinson (Nobel of production whereby 1,633 billion units Prize in Chemistry, 1947, see also Chapter of penicillin were produced in 1944 alone. DQG ¿HUFHO\ GHIHQGHG E\ KLP DV ZHOO The tremendous effort extended towards as by a number of other notable chemists the development of penicillin may be less such as Sir John Cornforth (Nobel Prize in familiar to us than the Manhattan Project, Chemistry, 1975). Its ơ-lactam rival was but it is easy to argue that the former col- advocated by Merck scientists and by the ODERUDWLRQ\LHOGHGIDUJUHDWHUEHQH¿WVWR Oxford axis of Abraham and Chain. Despite

103 Chapter 13 Box 5 Sheehan’s thoughts on the total synthesis of penicillin V

an indispensable step during the construction of bacterial cell walls (Box 4). The acylation process deactivates this cross- linking enzyme, thereby compromising the integrity of the bacterial cell wall, resulting $WWKHWLPHRIP\VXFFHVVIXO in rapid cell death. Unlike bacteria, only a V\QWKHVLVRISHQLFLOOLQ9LQ phospholipid membrane surrounds mam- malian cells, so transpeptidase inhibition is ,FRPSDUHGWKHSUREOHPRIWU\LQJ experimental evidence for the existence of completely selective for bacterial cells. It WRV\QWKHVL]HSHQLFLOOLQE\FODV a ơ-lactam structural motif provided by has been shown that the penicillin molecule the Merck scientists, conventional wisdom adopts an overall conformation that is very VLFDOPHWKRGVWRWKDWRIDWWHPSW could not accept the presence of such a similar to the D-alanine-D-alanine residue LQJWRUHSDLUWKHPDLQVSULQJRI strained and reactive feature within a of the substrate involved in this chain elon- naturally occurring substance. It was only gation process, thus it gains ready access DILQHZDWFKZLWKDEODFNVPLWKV after the brilliant crystallographic work of to the active site of the enzyme where it DQYLOKDPPHUDQGWRQJV Dorothy Crowfoot Hodgkin that the dispute reacts to disable its host. ZDV¿QDOO\VHWWOHGLQIDYRURIWKHơ-lactam The biosynthesis of penicillin, including structure in 1945, pleasing its backers and the unprecedented ơ-lactam ring, was elu- -RKQ&6KHHKDQ winning fame for the unobtrusive crystal- cidated through a series of brilliant chemi- lographer from Oxford. cal and biological studies, many of which The striking four-membered ơ-lactam were carried out by Sir Jack E. Baldwin and ring of penicillin, which was so decisively his group at Oxford University. In addition revealed by Hodgkin’s crystallographic to this seminal work, Baldwin is also known analysis, also turned out to be the motif for his contributions to biomimetic synthe- that was responsible for the lethal action of sis, as well as for a set of rules he devised Box 6 Sheehan’s total synthesis of penicillin V the drug against bacteria. This activity was to predict the outcome of certain ring-clos- found to be related to the conformation ing reactions. adopted by penicillin, wherein the fused Ironically, while the biological activ- 4,5-ring system enforces an orthogonal ity of penicillin relies on the characteristic alignment of the nitrogen lone pair and lability of the ơ-lactam ring, it is this same the carbonyl -bond such that the reso- feature that led most synthetic organic nance stabilization exhibited by traditional chemists of the wartime period to consider amides cannot be attained in this case. This penicillin an impossible target to conquer feature, in combination with the intrinsic by chemical synthesis. Indeed, despite a strain of the four-membered ring, creates huge effort directed towards its synthesis, a situation where the carbonyl functionality ERWKGXULQJDQGDIWHU:RUOG:DU,,QRVXF- of the ơ-lactam ring acts as a highly effec- cess was reported until much later. Indeed, tive acylating agent due to its particularly it was 1957 before John C. Sheehan at the strong electrophilic reactivity. Thus, it is Massachusetts Institute of Technology now known that penicillin irreversibly acyl- (USA) was able to announce triumphantly ates the bacterial transpeptidase enzyme the total synthesis of penicillin V, the result responsible for the cross-linking reaction of a relentless ten-year campaign (Boxes which unites the terminal glycine residue 5 and 6). of a pentaglycine strand with the D-alanine Sheehan’s celebrated success was due residue of a neighboring pentapeptide, in to his innovative and daring approach. He

104 Penicillin had recognized very early on that the main hurdle to be overcome prior to any total synthesis of penicillin was the construction of the highly strained and sensitive ơ-lactam ring. In addition, it was clear to him that a suitable method for accomplishing this challenging ring formation had to be developed since none of the existing technologies could be expected to rise to the to Sheehan’s DCC coupling conditions pro- Ball and stick model challenge. It is here that Sheehan’s insight vided penicillin V as its potassium salt. So of the molecule of and brilliance ensured his team’s triumph. - LWZDVWKDWWKH¿UVWWRWDOV\QWKHVLVRISHQL penicillin G He conceived of and developed the N,Nߙ- cillin was accomplished, a milestone event dicyclohexylcarbodiimide (DCC)-mediated in the history of the art of total synthesis. coupling of carboxylic acids with amines This feat marked not only the beginning of to afford amides. Applied in its intramolec- a highly productive era in the synthesis of ular version (wherein the amine and acid ơ-lactam derivatives, many of which were both belong to the same molecule) on an subsequently synthesized, but also repre- appropriately functionalized precursor, sented the addition of a new dimension to this method would solve one of the most total synthesis endeavors, that of seek- recalcitrant problems in chemical synthe- ing to invent new synthetic technologies Sir Jack E. Baldwin sis of the 1940s and 1950s – the construc- along the way. The task of developing this tion of the ơ-lactam ring of penicillin. The paradigm further, taking it to impressive DCC coupling reaction, later extended to new heights, would be assumed by one provide a solution for ester bond forma- of Sheehan’s students, the now highly cel- Ribbon model of isopenicillin N-synthase tion, remains a powerful synthetic tool ebrated master of this science E. J. Corey, in contemporary organic synthesis, and about whom we will learn much more later has been the inspiration for many simi- in subsequent chapters. lar reactions. This innovation was not the Penicillin ushered in a new epoch in only one made by Sheehan during the antibiotic research, one that grew by leaps penicillin synthesis; the phthaloyl protect- and bounds over the ensuing decades. A ing group for primary amines was another series of new naturally occurring ơ-lactams important and enduring contribution ema- such as cephalosporin C, clavulanic acid, nating from his group. and thienamycin were delivered in quick :LWK WKHVH WZR LQQRYDWLRQV DW WKHLU succession for use as drugs (Box 7). As disposal, the Sheehan group was able to soon as these discoveries had been made complete the synthesis of this previously in microbiology laboratories, synthetic impossible target through the sequence chemists busily focused on synthesizing EULHÀ\RXWOLQHGLQ%R[7KXVFRXSOLQJRI the newly discovered natural products a phthaloyl-protected amino aldehyde with and modifying their structures in an effort a suitable amino thiol led to the construc- to discover new antibacterial agents with tion of the thiazolidine ring of penicillin. LPSURYHG SKDUPDFRORJLFDO SUR¿OHV 7KHLU Further elaboration furnished an advanced work led to an equally impressive collec- amino diacid intermediate which served as tion of synthetic or semisynthetic ơ-lactam the precursor for the ơ-lactam ring of peni- antibiotics including ampicillin, amoxycillin, cillin V. Indeed, exposure of this precursor and methicillin (Box 7). During this golden

105 Chapter 13 Box 7 Molecular structures of various -lactam antibiotics

and of the antibiotics used to defend us against them, will be revisited in the chapter introducing vancomycin (Chapter 31), a natural product that is today the lifesaving drug of last resort in cases of severe infection. :H PXVW FRQFOXGH WKLV DFFRXQW E\ era for antibiotics, however, came some underscoring once again the profound disturbing news. Their widespread use, VLJQL¿FDQFHRIWKHGLVFRYHU\RISHQLFLOOLQ and sometimes misuse, led to the rapid Besides constituting a landmark medical evolution and spread of antibiotic-resistant breakthrough that saved lives and allevi- bacterial strains. A new menace for human- ated human suffering, this fortunate event ity was now looming on the horizon! also revealed to scientists a new treasure Bacterial strains have evolved the trove of biologically active molecules capability to evade the action of ơ-lac- ripe for exploration. Thus, to the forest, tam antibiotics by producing an enzyme, which held the key to the development called ơ-lactamase, which can cleave of Aspirin®, we now add the kingdom of the ơ-lactam ring, thus deactivating the microbes as a rich hunting ground for molecules before they reach their site of molecules endowed with healing powers. action. To combat these newly acquired Indeed, many such molecules have since enemies, scientists have since sought out been isolated from the soil and other habi- and developed various novel antibacte- tats where bacteria and fungi hold sway rial agents; some of these powerful new and, from this bountiful harvest, scien- antibiotics came from nature and some tists have derived a host of ‘magic bullets’ emerged from totally manmade designs. and billion dollar drugs, as we shall see in The story of drug-resistant bacteria, forthcoming chapters.

University of Oxford