The coming of age of antibiotics: discovery and therapeutic value

Authors


Address for correspondence: Karen Bush, Department of Biology, Indiana University, Jordan Hall, 1001 East Third Street, Bloomington, Indiana 47405. karbush@indiana.edu

Abstract

Origins of antibiotic drug discovery are frequently traced to 1929 when Alexander Fleming recognized the antibacterial activity of a substance secreted by Penicillium notatum on a contaminated culture plate. However, the subsequent development of penicillin as a therapeutic agent was not realized until the early 1940s, after a consortium of academic and pharmaceutical scientists from England and the United States developed sufficiently advanced fermentation technology to produce high-purity penicillin in large enough quantities for medical supplies. It was at this time that the antibiotic era was truly successfully launched. During the following decade, unprecedented antibiotic research and development emerged in academic laboratories and the pharmaceutical industry, resulting in identification of most of the antibiotic classes currently used therapeutically. This short historical commentary describes some of these early events, beginning with a conference held at the New York Academy of Sciences in 1946, the first conference to focus entirely on the latest science related to the identification and characterization of antibacterial substances produced by microorganisms.

In January 1946, a Conference on Antibiotics was held by the Section of Biology of the New York Academy of Sciences (NYAS) in which the discovery and clinical utility of antimicrobial agents were discussed. The conference proceedings were subsequently published in September 1946 by the Annals of the New York Academy of Sciences.1 Papers were presented by scientists from public, private, and governmental laboratories engaged in antibiotic discovery and development activities. Authors of the papers were from the Northern Regional Research Laboratory in Peoria, the University of Wisconsin, Columbia University, the New York Botanical Garden, Merck Research Laboratories, the Squibb Institute for Medical Research, Rutgers University, the Mayo Clinic, Halloran General Hospital in New York, Pennsylvania Hospital in Philadelphia, and the National Naval Medical Center.

It is especially noteworthy that the 1946 Annals volume included sections on both the microbiological and pharmacological aspects of antibiotics. Microbiologists had been documenting antagonistic activity from mixed cultures of microorganisms for many years. Beginning in 1877, Pasteur and Joubert2 observed that anthrax failed to develop in a robust manner in laboratory animals that were coinfected with Bacillus anthracis and other pathogenic bacteria; later studies demonstrated that such organisms as Pseudomonas aeruginosa or Streptococcus erysipelatis were capable of antagonizing the infecting properties of other bacteria.3 This antagonism between two microorganisms was later attributed to the ability of some bacteria to produce chemical substances capable of killing other microorganisms. However, the pharmacological principles of antibiotic action were not well understood or well studied until the early 1940s. Thus, clinical research relating to the effects of purified antibiotics in infectious diseases was still in its infancy at the time of this conference.

In his introductory remarks to the 1946 conference proceedings, Selman A. Waksman described the rapid establishment of antibiotic research as an active and productive area. He noted that in December 1940, only five years previously at a meeting of the Society of Bacteriologists, he was unable to identify enough participants for a two-hour roundtable discussion on the topic.4 Waksman was probably the most recognized investigator in the field at the time and was instrumental in defining the nomenclature and methodology that led to the identification of at least 18 antibiotics from his laboratory at Rutgers University during his career.5 It was Waksman who coined the term antibiotic to refer to substances produced by microorganisms that have the ability to kill bacteria.6,7 According to Waksman, antibiotics are pure natural products that produce both bacteriostatic and bactericidal effects. Today, however, the term has been expanded to include bacteriostatic antibacterial and antifungal agents that can be derived not only from natural products, but also from synthetic chemical approaches.

Antibiotic isolation and purification began in earnest around 1939. Waksman and his graduate student, H. Boyd Woodruff, developed the techniques to identify and isolate actinomycin in 1940 as one of the first antibiotics,8 followed by the isolation of streptothricin.9 In addition to these agents isolated in the Waksman laboratory,6 a number of other antibiotics were known by 1946, including the peptidic antibiotics gramicidin10 and bacitracin,11 which are still used in topical antibiotic ointments. However, the two antibiotics highlighted at the 1946 conference were penicillin and streptomycin, two agents that have retained at least some of their clinical utility over the past 65 years.

At the time of the conference, penicillin was the “wonder drug” that was considered to be useful in a wide variety of disease states, including infections caused by bacteria that were resistant to treatment with sulfonamides, the only other antimicrobial therapy available.12 At the conference, Duemling12 described the United States Navy's experience with penicillin based on a database of almost 18,000 sailors with 65 “different clinical entities” and noted that virtually no penicillin resistance was documented. Those patients who did not respond immediately were administered higher doses of penicillin and frequently had a successful outcome.12 However, concerns about the short half-life of penicillin abounded, and many attempts were made to prolong the pharmacological properties of the drug. One of the more creative approaches was described at the conference by the group from the Squibb Institute for Medical Research; they reported that it was possible to prolong the absorption of penicillin at the intramuscular injection site when the antibiotic was dissolved in a mixture of beeswax and peanut oil as initially described by Romansky and Rein,13,14 an approach used for a number of years thereafter to treat patients with venereal diseases.14 Later experience, however, revealed an unacceptable rate of allergic reactions, owing to the combination of responses to either peanuts, penicillin, or both,15 and the formulation was eventually discontinued.

Streptomycin was the focus of the other half of the 1946 NYAS conference, in which papers were presented describing the isolation of streptomycin from two different strains of Streptomyces griseus,16 the pharmacological properties of the drug,17 and the clinical applications of this aminoglycoside.18,19 It is most remarkable that groups from three different medical centers were able to present clinical data for four different clinical indications on a compound that had been isolated less than three years previously by Albert Schatz, a graduate student of Waksman, and that these data were disclosed to the scientific community only two years before the NYAS conference.16,20 This abundance of data can be attributed to the strong collaborations formed between Waksman and the medical community, in addition to his business relationships with scientists at Merck who were responsible for producing sufficient quantities of the drug for clinical evaluation. Streptomycin was best recognized for its activity against tuberculosis, with an early demonstration of its activity against experimental infections, and later, clinical disease, by scientists at the Mayo Clinic, as described in the 1946 proceedings.18 Although this drug also demonstrated efficacy in wound infections, it was found to have limited utility against genitourinary and bacteremic infections caused by Gram-negative bacteria, in which resistance emerged rather rapidly, as reported by Hinshaw and Feldman at the meeting.18

The 1946 Annals volume documents how Waksman's work leading to the discovery and development of streptomycin was well recognized by his peers. Eventually, Waksman was awarded the Nobel Prize in Physiology or Medicine in 1952 for his work on streptomycin,21 the first antibiotic to demonstrate clinical efficacy against tuberculosis and that is still used in some parts of the world in combination therapy for the treatment of susceptible strains of Mycobacterium tuberculosis. According to the biography of Waksman on the Nobel Prize website (http://nobelprize.org/nobel_prizes/medicine/laureates/1952/waksman.html), in 1964, the streptomycin patent was regarded as one of the 10 “patents that shaped the world.”22 However, Waksman's widespread recognition and success had a negative side.

As the student who had actually isolated the compound, Albert Schatz believed that he should have shared in the financial and scientific rewards from the success of streptomycin. In 1950, he filed a lawsuit against Waksman and Rutgers University, requesting a share of the royalties from the sale of streptomycin to Merck, which had assigned the royalties to Rutgers and Waksman in a ratio of 80:20. Following a bitter exchange among the parties involved, an out-of-court settlement resulted in Waksman's sharing his royalties, with 3% assigned to Schatz, and 7% split among 28 former laboratory personnel.21,23 Schatz eventually left the area of antibiotic research and ended his career advocating nonfluoridation of water24 and the therapeutic advantage of proteolysis-chelation in the treatment of tooth decay.25 Eventually, Schatz was awarded the Rutgers medal in 1994 (from Rutgers University) for his role in the discovery of streptomycin.23

H.B. Woodruff, a former Waksman graduate student who co-authored a review paper in the 1946 volume describing antibiotic production from bacterial sources,3 subsequently had a notable career in the pharmaceutical industry. Woodruff, who isolated the less-successful actinomycin and spectrothricin antibiotics, joined Merck in 1942 as a research microbiologist and later became a recognized leader in the area of antibiotic discovery during his 50-year career at the company. His last paper was published in 2001, describing the isolation of the natural product oligomycin G.26 Woodruff's work at Merck involved the discovery, isolation, and characterization of some of the company's most important antibiotics. He was involved in the development of the cephamycin cefoxitin27 and in the discovery of thienamycin, a naturally occurring carbapenem that served as the precursor to the commercially successful imipenem.28

Technology has changed considerably in the past 65 years, but the papers in the 1946 Annals volume could be considered the basis for today's antibiotic discovery and development efforts. We are still trying to cure diseases that have no effective antimicrobial treatment, and we are still setting up collaborations among scientists who bring different skill sets to the tasks at hand. Many of the same concerns and issues that drove the development of penicillin and streptomycin are described in the papers included in the current Annals volume entitled Antimicrobial Therapeutics Reviews.

Although we no longer rely on natural product isolation to find new antibiotics, we do use natural product scaffolds for the synthesis of new antimicrobial agents, as described in the current paper by Gwynn et al. in this volume.29 The sophisticated technology used in structure-based drug design, as outlined by Agarwal and Fishwick,30 is an extension of the medicinal chemistry that has given us dozens of penicillin and aminoglycoside analogs based on compounds known in 1946. Antimicrobial peptides can be used as immunomodulators as shown by Nicholls et al.31 Bartlett clearly presents why Clostridium difficile infections have continued to be important, especially during the past decade,32 but isolates of various Clostridium spp. were considered to be target pathogens when streptomycin was being considered for clinical development.33 Although not addressed directly in the 1946 papers, identification of sensitive pathogens in infections, as described by Tenover,34 would make clinical success a greater probability. In spite of the limited number of antibiotics available in 1946, the practice of cycling antibiotics was alluded to during the Navy experience with penicillin and the sulfonamides,12 a practice that is carefully reviewed by Bal et al. in this volume.35 Finally, as we consider all the antibiotics that have been discovered and that have been used over the past 70 years, it is important to recognize that infectious diseases occur not only in humans, but also in veterinary animals. In this volume, Shryock and Richwine provide a healthy discussion concerning the judicious use of antibiotics in humans and animals.36

In order for the antibiotic age to continue along a successful path, it is necessary for us to remember the foundation of the science that brought us to this point. In spite of our vast armamentarium of antimicrobial agents, infectious diseases will continue to plague us with organisms that are becoming more and more resistant to the available agents. With our ingenuity and diligence, it is possible that we can provide new agents, as well as new therapeutic approaches to controlling, if not curing, most infectious diseases. These papers all describe tactics for us to consider as we move toward those goals.

Conflicts of interest

The author is a former, retired employee of Bristol-Myers Squibb, Wyeth, and Johnson & Johnson Pharmacetical Research & Development. The author has also consulted for the following companies: Anacor, Cempra, Cubist, Merck, Novexel, and Shionogi.

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