The Microbial World
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1-13 Antimicrobial compounds are developed to kill microorganisms
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[Prev] | [Next]- Paul Ehrlich spent 17 years in search of a chemical treatment against syphilis, eventually discovering salvarsan.
- Alexander Fleming discovered the first antibiotic, penicillin.
We now pick up another thread though the web of microbial history that began with the work of Paul Ehrlich. By 1885, it was becoming clear that the causative agents of many illnesses were microorganisms. As scientists manipulated these microbes in the lab they found that certain dyes and other compounds were able to inhibit their growth. This inspired Paul Ehrlich to propose that chemicals may exist that kill the microbe, but not the patient, thus curing the illness.
One of the diseases Ehrlich hoped to cure was syphilis, which had reached epidemic proportions in Europe. Little did he realize it would be a 17-year odyssey before he would develop salvarsan, the first effective chemotherapeutic agent. Salvarsan was the 606th chemical he tried. This arsenic compound effectively kills Treponema pallidum, the causative agent of syphilis.
The treatment, however, had many problems, causing long lasting health complications for those individuals who used it. In addition, despite Treponema being quite sensitive to salvarsan, the physician had to administer it intravenously for optimum effectiveness. Intravenous injection was a recent development and many doctors were leery of trying the procedure. In London, a young physician by the name of Alexander Fleming, then in the Army Medical Corps, was one of the few that was willing to treat patients. Fleming even got the nickname private 606 from his burgeoning practice. His work validated the effectiveness of salvarsan against syphilis and convinced others to administer the treatment.
Fleming, pictured in Figure 1-9, was a physician by training, but spent most of his time studying bacteria, and his success with salvarsan motivated him to search for other antibacterial agents. His first discovery was lysozyme, an enzyme produced by many organisms including humans, which lysed some bacteria. This enzyme is not useful as a therapeutic agent because it is difficult to administer as a drug, but Fleming did develop titration methods and assays that would become very useful.
Figure 1-9 Alexander Fleming
A young English physician who discovered the antibiotic penicillin. Drawing by Tammi Henke
Fleming's arguably most important contribution to science is his discovery of penicillin. In September of 1928, before leaving on a summer holiday, Fleming streaked some plates of Staphylococcus aureus and left them to incubate until his return. In an improbable set of circumstances, the beginning of the holiday was cold, allowing some contaminating mold spores (that had blown in from a nearby window) to grow up on some of the plates. The temperature then increased encouraging the growth of the Staphylococcus. Many experimenters when confronted with a contaminated plate look for the trash bin, but Fleming instead spent some time examining it. The fungus had a zone of clearing around it where the Staphylococcus colonies would not grow, suggesting the fungus was producing an antibacterial compound that had diffused into the medium. Intrigued, he cultured the fungus, a Penicillium mold, and eventually isolated a soluble extract that could kill bacteria and treat localized infection. He called the new compound penicillin after the mold from which it came. Due to the technology then available, however, it was very difficult to prepare a solution that could be used throughout the body without causing problems.
World War II added a greater urgency to the search for compounds that could fight infectious disease. Wounded soldiers, if they survived the initial injury, would often develop life-threatening infections and there were no effective drugs to combat them. In 1939 Howard Florey and Ernst Chain began a systematic study of antimicrobial compounds in hopes of developing treatments for these soldiers and ran across Fleming's report written 9 years earlier. They now were able to purify the compound completely and describe its high potency against microbes. The availability of penicillin during World War II saved countless lives. The rediscovery of penicillin touched off a search for other microbes producing substances that could kill or inhibit microbes, leading to the discovery of many more antimicrobials. With Florey and Chain, Fleming was awarded the Noble prize in Medicine and Physiology in 1945.
In the ensuing decades the search and discovery of numerous antimicrobial compounds, combined with the development of vaccines, has eliminated many of the deadly diseases that plagued humankind. While we now realize this is a continuing war and not a one-time battle, our understanding of these microbes and the nature of disease will likely keep infectious disease at bay for the foreseeable future. Figure 1-23 lists important events in the treatment and prevention of disease.
Figure 1-23 Treatment and prevention of disease
| Year | Event |
| 1100 | Physicians in India and China realize that the liquid from the pustules of a smallpox victim, when scratched on the skin of a healthy patient, would most often cause mild disease. This intentional infection, termed variolation, would also give life-long protection against the illness. |
| 1721 | Lady Mary Wortley Montgue, wife of the ambassador to the Ottoman Empire, introduces variolation to Europe. |
| 1796 | Edward Jenner uses cowpox to immunize against smallpox. |
| 1884 | Ilya Ilich Metchnikoff demonstrates that certain body cells move to damaged areas of the body where they consume bacteria and other foreign particles. He calls the process phagocytosis. This is the beginning of the science of immunology, the study of the immune system. |
| 1885 | Paul Ehrlich proposes that certain chemicals affect bacterial cells and begins a search for one that can treat syphilis. |
| 1886 | Theobald Smith and D. E. Salmon develop a treatment for hog cholera by injecting killed hog cholera microorganisms into pigeons and demonstrate immunity to subsequent administration of a live microbial culture of cholera. |
| 1891 | Ehrlich shows that antibodies are responsible for part of immunity. |
| 1897 | Almwroth Wright and David Sample develop an effective vaccine against typhoid fever using killed cells of Salmonella typhi. |
| 1897 | Waldemar Haffkine develops a vaccine against the plague. |
| 1912 | Paul Ehrlich announces the discovery of a cure for syphilis. The cure is the first specific chemotherapeutic agent for a bacterial disease. |
| 1929 | Alexander Fleming publishes the first paper describing penicillin. |
| 1935 | Gerhard J. Domagk uses Prontosil, a chemically synthesized antimetabolite, to kill Streptococcus in mice. |
| 1938 | Max Theiler produces a vaccine against yellow fever by passaging the virus through mice to weaken it. |
| 1940 | Howard Florey and Ernest Chain produce an extract of penicillin and show it can kill bacteria in animals. |
| 1940 | Ernest Chain and E.P. Abraham describe a substance from E. coli that can inactivate penicillin. This demonstrates how rapidly bacteria can become resistant to antibiotics. |
| 1940 | Selman Waksman and H. Boyd Woodruff discover actinomycin, the first antibiotic obtained pure from a group of soil organisms, the actinomycetes. In subsequent years many antibiotics are isolated from this group including tetracycline and streptomycin. |
| 1941 | Charles Fletcher demonstrates that penicillin is non-toxic to human volunteers, by injecting a police officer suffering from a lethal infection. |
| 1942 | Selman Waksman suggests the word "antibiotic" to describe the class of compounds produced by one microorganism that inhibit or kill other microorganisms. |
| 1944 | Albert Schatz, E. Bugie, and Selman Waksman discover streptomycin, a very effective drug against tuberculosis. |
| 1944 | W. H. Feldman and H. C. Hinshaw at the Mayo Clinic successfully treat tuberculosis with streptomycin. |
| 1957 | The Soviet delegation to the World Health Organization proposes a vaccination effort to eradicate smallpox. The program finally begins in 1967. |
| 1977 | Ali Maow Maalin, age 23 of Somalia, is the last known victim of naturally occurring smallpox. |
| 1979 | Smallpox is declared to be eliminated. This is the only example of a microbial disease that has been wiped from the face of the Earth. (However, the recent specter of bioterrorism and the smallpox stocks kept by several governments make new epidemics of smallpox still possible.) |
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