Lect24: After Penicillin

After Penicillin

Introduction

With the discovery of a means of producing large quantities of penicillin, and the successful treatment of once fatal infections and diseases, a concerted effort was begun to search for more antibiotics. The search was expanded to include other fungi, as well as algae, animals, bacteria and plants. Although none of the antibiotics discovered, since penicillin, have had the same notoriety, many are just as important and many are more commonly used than penicillin, especially the over-the-counter antibiotics used as topical applications. Most have been bacterial metabolites, or more specifically, Actinomycetes, which are mycelial producing bacteria that were once thought to be fungi. The most well known, discovered antibiotic, following penicillin was probably streptomycin.

As was the case in the discovery of penicillin, the brief summary of the discovery of streptomycin, presented in text books, does not tell the entire story. What is generally told is that the discovery of streptomycin is credited to Selman Waksman, a soil microbiologist, who began his research, in 1915, on the effects of fungi and bacteria on the fertility of soil. However, Waksman would change the direction of his research twenty four years later, when inspired by Florey and Chain's research with penicillin, as well as that of René Dubos' discovery of the first clinical antibiotic, tyrothricin that Waksman would begin a systematic search for other antibiotics. This eventually lead to the discovery of streptomycin. Test carried out with streptomycin indicated that it was active against a number of bacterial disease organisms, which was not affected by penicillin. These included Mycobacterium tuberculosis, the cause of tuberculosis; Klebsiella pneumonia, the cause of walking pneumonia; Shigella gallinarum, the cause of fowl typhoid; Salmonella scottmuleri, one of the causes of food poisoning; and Brucella abortus and Proteus vulgaris, two microbes responsible for urinary infections. This discovery would eventually lead to the 1952 Nobel Prize, in Physiology or Medicine, for Selman Waksman. Although Actinomycetes are no longer classified as fungi, the detailed story of streptomycin, one of the most important antibiotics isolated from Actinomycetes, is a very interesting one that parallels the research that was done with penicillin, but with a far different outcome for the two people involved in the discovery of streptomycin. This story, in facts, shows the darker side of scientific research and raises the question as to who should be credited for scientific discoveries.

The Story of the Discovery of Streptomycin

As in the case of the discovery of penicillin, the story can be rather complex and who should be credited for the discovery is one that is argued, even today, and for those of you who are interested in going to graduate school after your undergraduate degree, may find this story to be of interest.

In much of the literature concerning streptomycin, the discovery of streptomycin is almost credited entirely to Selman Waksman. Waksman would also be credited with the discovery of a number of other antibiotics and would become very prominent in the field of antibiotics (Rubin, 2007). However, in the discovery of streptomycin, there was, and still is, a great deal of controversy with respect to who should be credited with its discovery. Historically, there has been some mention of Albert Schatz as playing a role in this discovery, but he is not credited at all in Waksman's autobiography, with respect to being the person who actually isolated and discovered the antibacterial activities of streptomycin (Wainwright, 1990).

Even before the discovery of streptomycin, Waksman was an internationally known researcher in the field of soil microbiology (Rubin, 2007). However, his interest in antibiotics did not begin until 1938-39, due to the many discussions that he had with one of his former students, René Dubos, who had received highly, critical acclaim that during the International Microbiological Congress, in New York, on his isolation of the antibiotic tyrothricin, from the bacterium Bacillus brevis. Unfortunately, tyrothricin would eventually be demonstrated to be too toxic to be administered administered internally, for systemic infections, but could be safely applied topically for localized infections. However, it was this discovery that was one of the influences that started Florey's lab in working with penicillin and also ignited the change in direction of Waksman's research into the his search for new antibiotics from Actinomycetes (Cooper, 2007). According to Dubos, Waksman did not have any interest in this area of research before 1940 (Cooper, 2007). However, Waksman would soon develop a screening method by which he would screen large number of Actinomycetes species with selected pathogenic species of bacteria. The method he used was a "shotgun approach" that is still used today. Waksman tested each species species for the ability to produce antibiotic activity by introducing bacteria into these cultures and looking for evidence of inhibition. Also, while I have been using the term "antibiotic" freely here as well as in our discussion with penicillin, it was Waksman who actually coined this term in 1941 (Cooper, 2007). Waksman would have a number of graduate students that would screen for antibiotics and one of them was Albert Schatz. Schatz would be the one that would isolate the antibiotic streptomycin from Streptomyces griseus.

It was in June of 1942, Albert Schatz began his graduate work as a student of Waksman and was given a research project unrelated to streptomycin. However, this was during World War II and by November of that year he was drafted into the army and became a laboratory technician in the Medical Detachment of the Air Corps, stationed at an army hospital in Florida. It was during this time that he began looking for antibiotics that would be useful against bacterial diseases resistant to penicillin. However, his stay in the army was a short one, and in June 1943, Schatz was discharged due to a congenital back problem. He immediately returned to graduate school as a research assistant to Waksman, for $40.00 a month. However, now Schatz was doing research on finding antibiotics that would be effective against pathogens resistant to penicillin, research that he had already started in the army. It was about this time that Waksman received a visit from William Feldman and H. Corwin Hinshaw, of the Mayo Clinic, in Rochester, Minnesota. They wanted to do some collaborative work with Waksman on clavacin, an antibiotic that Waksman had already isolated and test it against Mycobacterium tuberculosis, the cause of tuberculosis (also commonly called TB, consumption or the white plague). At this time, this disease was killing millions of people each year and Drs. Feldman and Hinshaw were two of many researchers working on a way to stop this disease. However, at this time all of the antibiotics that Waksman had isolated were too toxic to be used and clavacin was no exception. Whether this was what prompted Waksman to add M. tuberculosis to the disease causing bacteria that Schatz was already testing or not is not known. Whatever, the reason, Schatz did include M. tuberculosis and used a strain that was particularly virulent. This was of concern to Waksman and for that reason, he moved Schatz to a laboratory work space, in the basement, where he would be isolated from the rest of the building in the event that the M. tuberculosis bacterium should escape in the lab (Rubin, 2007). It was also for that reason that Waksman never came down to see Schatz. Instead, if he wanted an update on the progress of Schatz's research, he would ask him to come to his office. The search for a new antibiotic that would be effective against the various pathogens that he was testing could have lasted years, but Schatz was fortunate in that he succeeded in isolating an Actinomycete, Actinomyces griseus, now Streptomyces griseus that produced an antibiotic that was effective against a wide range of pathogens, including M. tuberculosis.

Schatz would receive his Ph.D. for his work on streptomycin and Waksman would allow Schatz to be the first author in a paper published, in 1944, in The Proceedings of the Society for Experimental Biology and Medicine, titled "Streptomycin: a Substance Exhibiting Antibiotic Activity Against Gram Positive and Gram Negative Bacteria." The second name on the paper was Elizabeth Bugie and Waksman was the last name on the paper. The order in which the names appear is important in scientific papers. However, their interpretation can have different meanings. Generally, the first name on the paper is the person who has made the greatest contribution to the research, but it is also not unusual for many researcher supervising a Ph.D. student, to place their name last in order to enhance the career of the student.

It should also be noted that while the discovery of streptomycin was attributed to Waksman, or Waksman and Schatz, there were two other researchers involved. Neither Waksman or Schatz were qualified to carry out experiments with animals (this was also the case with Alexander Fleming) and the next phase of the development of streptomycin should have been credited to the two research physicians, Feldman and Hinshaw that visited Waksman concerning collaborative work on clavacin and tuberculosis. After Schatz had demonstrated the effectiveness of streptomycin against all of the pathogens he used as test organisms, Waksman contacted Feldman and Hinshaw about testing the antibiotic on tuberculosis. They were the ones that carried out experiments, first with infected guinea pigs, followed by tests on human subjects, both proved successful in treating tuberculosis.

The question as to who should receive credit, however, did not come about until several years after Schatz had graduated from Rutgers with his Ph.D. The relationship between Waksman and Schatz, in fact, had been very amicable the entire time Schatz was Waksman's student and for a time after Schatz had received his Ph.D. Before leaving Rutgers, a patent was awarded to Waksman and Schatz, in 1948, for streptomycin, and a gentlemen's agreement was made that neither would profit from this discovery, and that all royalties for the discovery of streptomycin would go to the Rutgers Research Foundation. It was not until 1949 that problems began. Schatz by this time was at Hopkins Marine Station, Pacific Grove, in California. While there Schatz wrote letters to Waksman for advice concerning his career and the relationship continued to be a friendly one. However, during this time Waksman had sent documents to Schatz that would sign away his rights to credit and royalties to streptomycin. In one of Schatz's letter, he suddenly confronted Waksman with the reason for signing the document and more importantly if any individual was profiting from the large profits that were being made in the sales of streptomycin. Schatz was to learn that Waksman had worked out a separate deal with Rutgers and was getting 20% of the royalties from streptomycin and by that time had already received approximately $350,000. In addition, he also received $35,000 from Merck, as a retainer.

When this deception was discovered, there were numerous exchanges between Waksman and Schatz that were less than friendly. This eventually led to Schatz suing Waksman and Rutgers, which caused considerable embarrassment to Rutgers, as well as to the scientific community as a whole. The latter sided with Waksman. However, the case would not be decided in an open court. Instead it was settled behind closed doors in the judge's chamber. The Judge's ruling was that Schatz be given credit as the co-discoverer of streptomycin as well as 3% of the royalties. Waksman received 10%, while Rutgers received the lion's share of 80%. The remaining 7% was distributed to all of the students and researchers who participated in the research for antibiotics at Rutgers. Only Feldman refused any payment from this discovery. Although it appeared that Schatz had won out, it was not to be. Schatz would receive $125,000, in the settlement, of which his attorney took 40%. What was far more damaging was that the lawsuit had cost him research positions. He was perceived by the scientific community as resentful and jealous because he had challenged Waksman and Rutgers. Thus, Schatz was essentially "black-balled" by the scientific community for a number of years.

Although Schatz had now received legal credit, as co-developer of streptomycin, when the Nobel committee came to Rutgers in 1951, Waksman would take all of the credit for the development of streptomycin. The Nobel committee also considered the two doctors, Hinshaw and Feldman, from the Mayo Clinic, but Feldman was recovering from Tuberculosis, in a New Mexico sanitarium and Hinshaw had moved on to a new position in California. Thus, when the committee named the 1952 Nobel Prize award, for Physiology or Medicine, Only Waksman was credited for the discovery of streptomycin. As you might expect, Schatz was very upset about this award. Schatz sent letters to previous Nobel Prize winners, e.g., Fleming, Florey and Krebs, that was forwarded by the Dean of an agricultural college in Pennsylvania, where Schatz was employed at the time telling them that he was the co-discoverer of streptomycin. However, it was to no avail. Once the Nobel Committee has made an award, it will not be rescinded regardless of the circumstances.

Even after the settlement on the case against Waksman, Schatz would still be largely unknown, in the United States, and would continue to pursue recognition for the discovery of streptomycin . However, his only recognition came as foreign awards from France and a few South American universities. Nevertheless, he did make some useful contributions, but none on the scale of streptomycin, which Waksman would continue, until recently, to receive sole credit. It was not until 1988 that Schatz would finally receive proper recognition of his work with streptomycin. Dr. Milton Wainwright, a lecturer in Microbiology, at the University of Sheffield, wrote a short article, "Selman A. Waksman and the streptomycin controversy", in the Society of General Microbiology. Wainwright was doing research for a book that he was writing on the history of antibiotic, where he would include a chapter on the history of streptomycin. Schatz's cause was most recently championed by Dr. Ross M. Tucker, who is semi retired from the Mayo Clinic. Rutgers University would also address the wrong that it had done to Schatz by honoring him the Rutgers Medal, the university's highest honor, as the co discoverer of streptomycin, during the 50th anniversary of the event. Unfortunately, the most esteemed award, the Nobel Prize, will never be his. The Nobel Prize committee has indicated that it will not change its award to accommodate the injustice done to Schatz!

Given the above information, who should receive credit for the discovery of streptomycin? Lets summarize the contribution of the people that we have discussed: It was in Selman Waksman's lab where the research had taken place and he was the one who began and led the research program in screening for antibacterial activity in Actinomycetes, even if he did not do any of the research, himself. Waksman was also the one that got the grant money for the research and paid Schatz to do the research that eventually led to streptomycin. However, it was Albert Schatz who actually isolated streptomycin from Streptomyces griseus, determined its antibiotic properties and had the expertise to work with pathogenic bacteria that he learned while in the military. It was his work that led to it being produced in large enough quantities that would enable medical researchers to properly evaluate streptomycin. Waksman, in fact rarely had anything to do with the actual research because he did not want to be in the same laboratory with active cultures of M. tuberculosis and other such disease organisms. Finally, it was the research carried out by Feldman and Hinshaw that actually determined its usefulness in medical applications.

Who Should Be Credited With The Discovery Of Streptomycin?

Who should be credited with the discovery? The inevitable comparison that can be made is with the discovery of penicillin, where the Nobel Prize was awarded to three people that each contributed to the eventual application of penicillin that would save millions. During the development of penicillin as the first commercially successful antibiotics, Howard Florey and Ernst Chain had a very strained relationship. Chain was of the opinion that he was the one that decided on carrying out research with penicillin, thought up all the experiments and generally did most of the work in the lab, while Florey was taking all of the credit (Rubin, 2007). Later when Fleming began working with Florey, their relationship would become strained as well. However, in the end all three were credited with the development of penicillin and all were named the recipient of the Nobel Prize in Physiology or Medicine, for 1945.

Similarly, Waksman and Schatz had a very amicable relationship until they went their separate ways, when Schatz took a postdoctoral position in California. However, upon Schatz's discovery that Waksman was receiving payment for the discovery of streptomycin, after both agree that neither would benefit from this discovery, their relationship deteriorated. Schatz would also begin to criticize Waysman for taking all of the credit for streptomycin. Whereas the parties involved in the discovery of penicillin as a practical means of treating systemic infections/diseases had settled their differences, Schatz and Waysman would not. Their feud continued to escalate and they would become life-long enemies.

Lets review the contribution of both men. Waksman was of the opinion that he made the major contribution because it was his intellectual contribution that directed his lab to this research area and he was the one that obtained funding for the research, which paid his student to do the work. From his point of view, he had directed the students' research and they were compensated through their employment, and that he, and he alone, deserved the credit. This is not the opinion in every researcher's lab, but it is in some. Schatz, on the other hand, believed that while he was paid to do research under Waksman, it was he who began to develop his research while still in the military and was it was also his idea to include M. tuberculosis as one of the disease organisms that he would screen for antibacterial activities. He also had to carry out his research without supervision because Waksman had segregated him from the rest of his lab because of his fear that the M. tuberculosis might escape containment. Following the completion of his research Schatz was first author on the publication in the isolation and discovery of streptomycin and its antibacterial activity. That Schatz was first author was very meaningful since. Waksman had previously never allowed his student to be first author on any paper. This led to the conclusion that Schatz was awarded this honor because he must have been a substantial contribution to the research to the research on streptomycin. Waksman would later claim that he was merely trying to aide Schatz in his career by allowing him to be first author. However, Waksman's claim would be met with some skepticism since it would have been unusually generous of him to do that since he had never previously bestowed this honor to other students. In addition, Schatz's dissertation was entirely on his research with streptomycin and he was also listed on the patent as the co-discoverer of streptomycin. It can readily be seen that both men made substantial contributions to the discovery of streptomycin and in my opinion both should have been credits with the discovery of streptomycin, including sharing of the Nobel Prize that was only awarded to Waysman. Unfortunately, this was not the case and Schatz would spend much of his life living under the cloud as a disloyal and greedy colleague and attempting to clear his name, as well as to receive his due credit as the co-discoverer to streptomycin.

Schatz only recently was acknowledged as the person who discovered streptomycin through the effort of Milton Wainwright. While researching the history of the discovery of streptomycin, Wainwright visited Rutgers University where streptomycin was discovered, and in searching through the archives, scientific papers and interviews with faculty, staff and former students, as well as Schatz, concluded that Albert Schatz had been "gravely wronged" in not receiving credit for this discovery (Mistiaen, 2002). Schatz's contribution was told in Wainwright's book (Wainwright 1990) and in some of his journal articles (Wainwright, 1988; 2005), as well as by Lawrence (2002) and often by Schatz, himself (Schatz, 1993). It was also through the efforts of Wainwright that some faculty members also requested to the Rutgers' administration that Schatz be given credit for the discovery of streptomycin and in 1994, he received the Rutgers University Medal, the university’s highest honor, on the occasion of the 50th anniversary of the discovery of streptomycin. However, there are still those that believe that the salary that he was paid by Waksman to do research, as well as the privilege of being able to carry out research in Waksman's lab was all that he deserved (Kinston, 2004).

Other Antibiotic Benefits of Actinomycetes

Since the discovery of penicillin and streptomycin, there have been thousands of antibiotics that have been discovered. Unfortunately, most would prove to be more toxic than the disease they were met to treat. However, there are a number that have been proved useful and have, as in the case of penicillin and streptomycin, saved millions of lives. We will cover just a handful of antibiotics that have been isolated. Not all can be taken intravenously or orally because of their toxicity, but have still proved valuable for topical usage. Some examples are over the counter anitibiotics such as Bacitracin and Neosporin.

Further Discoveries of Antibiotics

With the discovery of first penicillin and later streptomycin, scientists and drug companies obtained soil samples from all over the world to test for antibacterial activities. However, the pharmaceutical companies apparently were not so committed to this line of research that they wanted to fund travel to obtain soil samples. Instead, they began by begging airline pilots, missionaries, traveling salesmen, vacationers and soldiers to bring back soil samples. It was in this way that Chas. Pfizer & Co., who would become one of the largest drug manufacturers, built up a culture library of more than 20,000 samples, and each sample was isolated and tested in the same matter that Waksman tested his various Actinomycetes cultures. The cultures of the fungi being tested is inoculated with various pathogenic bacteria to determine if an antagonistic response occurs between the two organisms, i.e., the fungus is inhibiting the bacterial growth in some fashion. If the fungus does demonstrate anti-bacterial activities, testing with laboratory animals are then carried out, to determine if the metabolite is harmful or even lethal to the animals. Most fungal antibiotics tested have proven to be as lethal as the disease that they are trying to stop. However, a number of very useful antibiotics have also been found.

It was over the first ten years that most of the marketable antibiotics would be discovered, but new antibiotics continue to be found, even now (see Table below).

With the discovery that antibiotic production in microorganisms is widespread, the question as to their role in nature was pondered. It has been suggested that perhaps antibiotics play an active role for the microorganism in nature, such as acting as an inhibiting agent against other organisms, but little research has been carried out. Eventually, with the continued testing of various organisms, scientist began to find the same antibiotics over and over again and this line of research would be largely de-emphasized, in many pharmaceutical companies. A new kind of research then took place in which existing antibiotics were altered in the laboratory in an effort to improve then. This is how tetracycline, a now commonly used antibiotic was produced. It is sold under the commercial name of Tetracyn and Achromycin. In 1959, this approach led to the isolation of the "core" of the penicillin molecule, which made it possible for scientist to construct a whole series of penicillin, in the laboratory (Berdy, 2005).

Although, the search for antibiotics, from microorganisms, was de-emphasized, it remained very keen throughout the world. In 1961 the number of described antibiotics was 513. There were 4076 in 1972 and by 1989, there were 8000. There have also been 3000 additional antibiotic substances identified for lichens, algae, higher animals and plants. There are approximately 300 new antibiotic described annually. Pharmaceutical companies are always on the alert for possible new sources, regardless of how remote. While I was a graduate student at the University of California at Davis, I was working for Dr. Kenneth Wells, on several grants in which we isolates spores, from numerous species of jelly fungi, for the purpose of carrying out mating studies. These cultures had been maintained at Davis, until Ken retired. At which time a pharmaceutical company asked for all of his cultures for the purpose of testing them for antibacterial activities. In the United States, there are still a handful of research programs that test metabolites from various organisms for antibacterial properties. Among these programs is Dr. Greg Paterson, who until recently, was a researcher, at the University of Hawaii, in the Chemistry Department. Dr. Paterson is looking for antibiotics in algae, and a group of bacteria commonly referred to as blue green algae. Although, there are large number of antibacterial compounds found each year, it should be reemphasized here that most of these are as toxic to the guinea pigs as they are to the bacterial that they are testing.

Economic Aspects

There are 100,000 tons of antibiotics produced, world-wide, each year, with gross sales that amount to $4.2 billion, in1980. The annual gross, in the United States alone is $1 billion. Most of the sales involve cephalosporin, ampicillin and tetracyclines. Note that penicillin is absent from this list, and even though it is the most well known and its use is still very important in medicine, it is not among the top three antibiotics, with respect to sales. Although the antibiotics that are, in use, are of great economic significance, a great deal of expenditure is also utilized in the development of new antibiotics.

Prior to 1960, approximately less than 5% of the antibiotics developed were useful. In the following years, the number of antibiotics discovered remained constant, but the number of antibiotics that actually came on the market decreased to 2.6% between 1961-65, and between 1965-1971, dropped to 1%. The reason for the drop was due to cost. The average cost of developing an antibiotic is between $10,000,000-$20,000,000 and 8-10 years of time and resources. Thus, this decrease, in products being marketed, can be attributed to increase in cost of development and clinical testing, and other resources utilized in developing antibiotics. The pharmaceutical manufacturers now only market those products that they believe will be most clearly of value in therapeutic treatment.

The high cost and the large number of antibiotics now available have led some to question the search for further antibiotics. However, the continuation of antibiotic searches is justified for the following reasons:

• Lack of optimal antibiotic for therapeutic application: Some of the current antibiotics in use have harmful side effects, are somewhat toxic and/or are not as effective as desired.

• There are still many diseases in which antibiotics are not available for treatment.

• Due to the continual use of antibiotics, strains of bacteria resistant to these antibiotics are constantly being formed through genetic recombination. The rate of increase has developed rapidly through careless use of antibiotics, but even through careful use, resistant strains would still develop, even though it would be at a slower rate. One alternative to treating these resistant strains is through the development of new antibiotics.

Although there has been much to-do about how the search for antibiotics is for humanitarian purposes, most who have carried out research in this area have been more than compensated in terms of monetary gains, and making it more difficult to believe is that on more than several occasions, law suits have come about as to who should be credited and compensated for the discovery of antibiotics. Finally, it is of interest to note that during the early development of antibiotics, the iron curtain countries did not play a role in antibiotic development, leaving one to assume that the capitalistic system must have in some way serve as a stimulus for their development.

Application of Antibiotics

There are various schemes by which antibiotics can be classified: according to the specific organisms that they can affect, the mechanism by which they affect microorganisms, their chemical structure and the biosynthetic pathway. A system has also been devised to make it comprehensible to the nonscientist, and will be the one that we will use to demonstrate the various means by which antibiotics can be used. Note that the examples of category below, the definition of antibiotic is considerably broader than the one we definite.

Chemotherapeutic Antibiotics: This is the use of antibiotics for treatment of diseases, and the one with which we are familiar. This category can be divided into two subcategories: broad-spectrum antibiotics, those that are active against many organisms and narrow-spectrum antibiotics that are active against only a restricted number of organisms.

Antibiotics for Plant Pathology: Prior to the era of antibiotics, synthetic chemicals were used to treat plant diseases. Now antibiotics have been deemed more useful. They have the advantage of low toxicity to warm blooded animals and beneficial insects, are easily degraded by microorganisms and as in medicine, are effective in low concentrations. The first antibiotics used were the same as those used in medicine, but because such extensive use of antibiotics leads to a more rapid development of bacterial resistance to common antibiotics, this practiced has been discontinued and antibiotics have now been developed that are specifically used to treat plant diseases.

Antibiotics as Food Preservatives: Although you are well aware of the use of preservatives in food, you are probably not aware that some are antibiotics. Some important examples include nisin, which is used for canned food, chlortetracine, utilized in maintaining freshness in fish and poultry.

Antibiotics as Growth Promoters in Animals and Veterinary Medicine: In livestock, the antibiotics are incorporated into the feed. The function of the antibiotics have been utilized to increase weight gain by altering the make-up of the bacteria in the digestive system. Chemotherapeutic antibiotics were, again, first used, but that practice has been discontinued. Antibiotics have been developed that are used, by veterinarians, only to treat animals.

Antitumor Antibiotics: Tumors occur as the result of uncontrolled cell growth in the body. Antibiotics in this category are used to stop or retard tumor growth. Most of these compounds are toxic, but with carefully controlled dosage, may be effective against certain kinds of tumors. This usage differs from the others in that it is not utilized to treat disease caused by bacteria or fungi.

Some Common Examples of Antibiotics Derived From Fungi and Actinomycetes

Cephalosporin

With the exception of penicillin, most antibiotics were derived from soil inhabiting microorganisms. However, another exception to this rule is cephalosporin. It was isolated from sewage. Cephalosporin was first isolated from Acremonium chrysogenum (Cephalosporium acremonium), in 1948 by Guy Newton and Edward Abraham at the Sir William Dunn School of Pathology at the University of Oxford. This species actually produced several antibiotics: cephalosporin C, cephalosporins P1 - P5 and penicillin N. This was also true with penicillin. However, that was not discovered until research on the chemistry of penicillin was worked on.

Cephalosporin has also been identified from other fungi such as Emericellopsis and Paecilomyces, two genera that are closely related to Penicillium. Like penicillin, cephalosporin is valuable because of its low toxicity and broad spectrum action against various diseases. In this way, cephalosporin is very similar to penicillin. It is also perhaps the most widely used antibiotics, and economically speaking, has about 29% of the antibiotic market. Cephalosporin is possibly the single most important group of antibiotics today and are equal in importance to penicillin.

The structure and mode of action of the cephalosporins is similar to that of penicillin. Cephalosporins affect bacterial growth by inhibiting cell wall synthesis and is a broad spectrum antibiotic.

Griseofulvin

Griseofulvin is the only fungal antibiotic that is effective against fungal infections of hair, nail and skin. The antibiotic was first isolated from Penicillium griseofulvum, but its properties were not recognized until its re-isolation from P. janczewski. It has since been isolated from a number of other species of Penicillium as well as from Khuskia oryzae, a species of fungus quite distinct and not related to any species of Penicillium. The commercial production of griseofulvin is derived from a much mutated strain of P. patulum.

Griseofulvin is a fungistatic antibiotic, that is it will inhibits fungal growth and does not kill fungi, i.e. it is not fungicidal, . It apparently can affect a wide range of fungi, but by no means does it inhibit growth of all or even most species of fungi. Unlike antibiotics that treat bacterial diseases, it does not remedy the disease immediately. Being fungistatic, it will only inhibit fungal growth, and griseofulvin must be taken, three times a day, for several weeks or months, depending on the specific dermatophytes involved. For example, in ring-worm, griseofulvin is taken for two to four weeks, while in cases where finger or toe nails are involved, treatment usually last for many months. In the latter situation, financial considerations must be taken into account because treatment with griseofulvin is quite expensive. Long-term treatment is required in order for sufficient new growth of nail and skin to take place. In the case of skin infection, enough time for the old skin to be sloughed off and replaced by new skin. Similarly, in nail infection, sufficient new growth in the infected nail must occur so that the infected portion may be cut-off. During the period of griseofulvin treatment, infection of the new skin or nail growth will not occur because of the fungistatic activity of the antibiotic. Although nontoxic, it is not without side effects. Gastrointestinal intolerance can occur, usually causing nausea and/or diarrhea. Headaches is also an occasional complaint.

Fusidic Acid

Fusidic Acid acts as a protein synthesis inhibitor in bacteria. It was first isolated from Fusidium coccineum (Deuteromycota), but has since been obtained from Mucor ramannianus (Zygomycota) and Isaria kogana (Deuteromycota). Used clinically on Gram-positive infection and mainly against penicillin-resistant Staphylococus bacteria. It was released for clinical use in 1962.

Amoxicillin

This probably one of the most commonly prescribed antibiotic for children. As my children were growing up, this was prescribed on a number of occasions when they were ill. It is a broad spectrum antibiotic that was released for clinical use in 1972. It is used in treating a number of infections, including anthrax, urinary infections, skin infections, pneumonia and lymne disease. A similar antibiotic that preceded it was ampicillin that was released for clinical use in 1961.

Neomycin

Neosporin is a commonly used topical antibiotic isolated from the Actinomycete, Streptomyces fradiae, in 1949 by Selman Waksman and his student Hubert Lechevalier at Rutgers University. While available without prescription, allergic reaction and toxicity is common.

Fusafungine

An antibiotic isolated from Fusarium lateriatum, in 1963. It is a narrow spectrum antibiotic that is primarily used for nasal and throat infections.

Patulin

An antibiotic isolated from Penicillium patulum, in 1943. When it was discovered, it was initially thought to be the first antiviral antibiotic and one that could relieve the symptoms of the common cold. This is an example of how an antibiotic was not rigorously tested prior to the release of information concerning its usage. Dr. W.E. Gye began testing it on himself, by touching a concentrated solution of patulin to his nasal passages and within an hour claimed that it had relieved his cold symptoms and by the following morning was feeling well enough to return to work. Similar tests were tried by two of Gye's colleagues with the same results. Once these results were made public, a large scale test was carried out, which was also very encouraging. Fifty four percent of the volunteers tested claimed to have had relieve from their colds within 48 hours and seem to indicate that his antibiotic was indeed able to relieve the common cold. News of its ability to cure the common cold was known by this time. However, two more control experiments were carried out with volunteers, this time the conclusion was quite different. It was concluded that patulin had no curative effect on the common cold, whatsoever. Further experiments later determined that patulin was, in fact, toxic.

Literature Cited

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Mistiaen, V. Time, and the great healer. The Guardian. November 1, 2002

Rubin, R.P. 2007. A Brief History of Great Discoveries in Pharmacology: In Celebration of the Centennial Anniversary of the Founding of the American Society of Pharmacology and Experimental Therapeutics. Pharmacological Reviews 59:289-259.

Schatz, A. 1993. The True Story of the Discovery OF Streptomycin. Actinomycetes 4: 27-39, Actinomycetes 4: 27-39,

Wainwright, W. 1990. Miracle Cure: The Story of Penicillin and the Golden Age of Antibiotics. Basil Blackwell, Oxford.

Wainwright, M. 2005. A Response to William Kingston, "Streptomycin, Schatz versus Waksman, and the Balance of Credit for Discovery. Journal of the History of Medicine and Allied Sciences. 60: 218-220.

Terms of Interest

Actinomycetes: Group of organisms, once classified as fungi, because of their filamentous growth, but now correctly classified as bacteria. Many antibiotics were isolated from this group of organisms, including streptomycin.

Broad-spectrum antibiotics: Antibiotics that are active against a wide number of species of organisms.

Feldman, William: One of two doctors who were working on a means of treating tuberculosis, and was eventually successful when they used streptomycin in treating tuberculosis.

Hinshaw, H. Corwin: One of two doctors who were working on a means of treating tuberculosis, and was eventually successful when they used streptomycin in treating tuberculosis.

Narrow-spectrum antibiotics: Antibiotics that are active against a few species of organisms.

Schatz, Albert: The person who isolated streptomycin and discovered its antibacterial properties against a large range of disease causing organisms, including the tuberculosis bacterium.

Streptomyces griseus: Species of Actinomycete from which the antibiotic streptomycin was isolated.

Waksman, Selman: The researcher in whose lab streptomycin was discovered. Until recently, Waksman was given sole credit for the discovery, and was awarded the 1952 Nobel Prize, in Medicine and Physiology for the discovery of streptomycin.

Some Questions of Interest

1. Who was, for a long time, the only person credited with the discovery of streptomycin?

2. What is the significance of streptomycin in comparison to penicillin?

3. Who should be credited with the discovery of streptomycin?

4. What group of organisms have we isolated most antibiotics from?

5. How is screening for antibiotics carried out?

6. Why do pharmaceutical companies give finding new antibiotics a low priority?

7. We have thousands of antibiotics that have been isolated and identified. Why are we still looking new antibiotics?

8. Why are we modifying existing antibiotics rather than looking for new ones?

9. What are “super bacteria” and why are they important?

10. What is the reason for the rise in super bacteria?