History of penicillin

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Discovery

Penicillin has been used throughout history to fight disease, but it was not until 1928 that it was officially discovered.[1] In 1928, Alexander Fleming was conducting a laboratory experiment, and incidentally ran into the fact that the Penicillium fungus had strong antibacterial properties. A list of significant events leading up to Fleming’s discovery follows:[2]

- 1640 John Parkington recommended using mold for treatment in his book on pharmacology - 1870 Sir John Scott Burdon-Sanderson observed that culture fluid covered with mould did not produce bacteria - 1871 Joseph Lister experimented with the antibacterial action on human tissue on what he called Penicillium glaucium - 1875 John Tyndall explained antibacterial action of the Penicillium fungus to the Royal Society - 1877 Louis Pasteur postulated that bacteria could kill other bacteria (anthrax bacilli) - 1897 Ernest Duchesne healed infected guinea pigs from typhoid using mould (Penicillium glaucium) - 1928 Sir Alexander Fleming discovered enzyme lysozyme and the antibiotic substance penicillin from the fungus Penicillium notatum

While Fleming’s discovery was a major step towards antibiotics, it was not until the 1940s that penicillin could be used as a medicine. [2] Howard Florey and Ernst Chain were able to develop upon Fleming’s findings and ultimately isolate the active ingredient, penicillin, and create pills used to fight bacterial infections.[2]

How It Works

Penicillin works by preventing cells from dividing. It does not allow them to synthesize cell wall, and thus when the cells attempt to duplicate, they rupture and end up killing themselves. Because penicillin has such a strong focus on a bacteria’s cell wall, it is far more effective on Gram-positive organisms. When a Gram-positive organism attempts to duplicate itself, it must create more cell wall and split off, the penicillin causes there not to be any new cell wall, and instead of duplicating, the cell will simply rupture, effectively killing it.[3]

Diseases Cured with Penicillin

Penicillin antibiotics are most effective against gram-positive bacteria, e.g. the genera bacillus, clostridium, streptococcus, and staphylococcus). There are many different bacterial infections, diseases, and conditions that have been combated with the help of Penicillin. Here is a brief list of examples: Chlamydia – Penicillin can be prescribed to pregnant women in order to prevent the child from contracting the disease as well.[4] Stomach Ulcers – Penicillin was found to be effective in controlling the effects of stomach ulcers.[4] Tooth Abscesses – Penicillin kills the bacteria responsible for causing these infections.[4] Step Throat and Scarlett Fever - caused by the Group A Streptococcus bacterium streptococcus pyogenes, which penicillin can kill. [5] [6] Staph Infections - can lead to amputation of affected limbs and appendages if left untreated, or even death in cases in which the infection enters the blood stream. Fortunately, Penicillin was found to be effective in killing staphylococcus aureus, the bacterial cause of the infections.[7] Leptospirosis (Weil’s Syndrome) – Can cause kidney and liver failure if left untreated.[8] Lyme Disease – Penicillin can help prevent the disease from spreading throughout the body; which could lead to further complications with the heart and nervous system in the later stages of the disease.[9] Typhoid Fever – can lead to kidney failure and eventually death if left untreated. Before penicillin, was much more widespread in the US; 35,000 reported cases during the 1920s, about 400 cases reported annually in modern times.[10] Gas Gangrene – can prevent further spread of this condition which is caused by a clostridium perfringens infection.[11] Necrotizing Fasciitis (Flesh-eating disease) – destroys soft tissues around infection site; will spread without treatment.[12]

While Penicillin antibiotics were at first extremely killing the bacteria that cause these diseases, the bacteria soon built up immunity to these antibiotics as they were overprescribed. Due to this, many bacterial strains are now resistant to Penicillin, and some of these diseases are no longer able to be treated using Penicillin antibiotics. This development has led pharmaceutical companies to have to produce new antibiotics that work in the same way as Penicillin antibiotics once did.


Developments from Penicillin

Although penicillin itself has a narrow spectrum of activity, virtually every antibiotic discovered or developed post- penicillin owes its existence to it. Not only do the penam sub-class of Beta- Lactam antibiotics stem directly from this first “miracle drug”; but the discovery of penicillin also ignited the desire in scientists to find and/ or develop other antibiotics as well (the first of which was streptomycin, which effectively cured Tuberculosis[13]). The penam subclass, which is the most widely used group of antibiotics[14], consists of penicillin and its derivatives- all of which end in “cillin” and possess a central Beta- Lactam ring structure. The penams can be broken up into two camps: Extended spectrum and Narrow spectrum antibiotics. The extended spectrum penams include amoxicillin, ampicillin, and mezlocillin, among others, and as their name suggest, these antibiotics work against very wide range of bacteria. Some extended spectrum penams (called antipseudomonal penicillins) even proved useful against Gram-negative bacterial cells, including pipericillin, carbenicillin, and ticarcillin.[15]

The Narrow spectrum antibiotics, on the other hand, act on a smaller, more specific group of bacteria. Narrow spectrum drugs can be broken up into those that are B- Lactamase sensitive (e.g.- benzylpenicillin, azidocillin) and those that are B- Lactamase resistant. B- Lactamase is an enzyme that many bacteria started producing as a means to resist the B- Lactam antibiotics. New antibiotics, the B- Lactamase resistant set, were then developed to combat the bacteria’s resistance to penicillin and penicillin- like drugs. Antibiotics that are resistant to the B- Lactamase enzyme, and thus can kill bacteria that the other penams cannot, include oxicillin, flucloxicillin, and methicillin; however, only two years after methicillin hit the market, strains of Staphylococcus aureus began exhibiting signs of resistance to it. Now Methicillin- resistant Staphylococcus aureus (MRSA) has become one of the infections most feared in hospitals and on athletic fields.

The Future of Penicillin

Bacteria are often able to become resistant to antibiotics quickly, which makes staying ahead of bacteria when developing antibiotics very difficult. What causes this is that when antibiotics are used such as penicillin, if there are any microbes left behind, they begin to repopulate with resistances to the antibiotic. These resistances easily come as microbes share their information about the antibiotics, which causes a need to develop more antibiotics; however this takes a lot of time and money and is not very profitable. Staphylococcus aureus is a gram-positive microbe that was the first bacteria penicillin was used against. The infection combated penicillin by acquiring an enzyme, B- Lactamse, that would snip the central ring of penicillin. By doing this, the microbe became resistant to penicillin and now most of Staphylococcus aureus cannot be fought with penicillin. Microbes can become resistant to antibiotics in a couple ways. If an infection alters a protein that the antibiotic uses to bind to in a spontaneous mutation, the antibiotic would not be able to work. Infections can also acquire new instructions. They can pick up new DNA that carries information allowing the bacteria to modify such as Staphylococcus Aureus did in its ability to snip the central ring of penicillin. New DNA can be shared between different species of bacteria and this sharing is often random however the microbes that gain the DNA leading to resistance will survive. This new DNA can be picked up from a dead cell, passed from cell to cell or transferred through viruses. There are also ways for us to combat the growing resistances of microbes. By limiting out own use of antibiotics, bacteria will have less exposure to the antibiotics. This would cause it to be more difficult for them to develop resistances. To do this, doctors must be educated to prescribe antibiotics only when they are actually needed. When antibiotics are prescribed for viruses they are not effective and only help microbes build up resistance to the microbes. Also patients should make sure to take the full course of antibiotics. When stopping taking antibiotics early or just when symptoms subside, there could still be a few infectious microbes left which would re populate with greater resistance to that antibiotic. There is also a lot of use of antibiotics on farm animals, which can cause a transfer of the animal’s resistances into us. Even with the growing resistance there is a declining development of new antibiotics for economic reasons. From 1983 to 1987 there were 16 new antibiotics made and approved by the FDA, from 2003-2007 there were 5, and since 2008 there have only been 2.[16] This is because there are now far fewer pharmaceutical companies investing in making new antibiotics because there are not profitable ways to produce new antibiotics. Top selling drugs in 2009 where Lipitor, Plavix, remicade, advair, Enbrel, avastin, ability, rituxan, humira, diovan, crestor, and lovenox.[16] None of these are antibiotics and all are used for chronic conditions which is a much more profitable field for developing drugs. In order to continue to develop new antibiotics there would need to be financial incentives for the companies to develop new antibiotics and increases in funding. Because this is unlikely there is not an expectation for many new antibiotics until there is a dire need which would create a profitable demand in the economy and become beneficial for companies to develop new antibiotics.

References

1. “Antibiotic- Penicillin,” Elmhurst College. Accessed May 7, 2012.

2. Bellis, Mary, “The History of Penicillin” About.com Inventors. Accessed May 8, 2012.

3. “History of Antibiotics” Experiment Resources. Accessed May 8, 2012.

4. Lietz, Jessica, “What Does Penicillin Treat,” EHow Facts, April 15, 2009. Accessed May 8, 2012.

5. Hill, McGraw, “Scarletina: Symptoms, Diagnosis, Treatments, and Causes” Sherris Medical Microbiology. Accessed May 6, 2012.

6."Strep Throat: Causes, Incidence and Risk Factors” US National Library of Medicine, November 18, 2000. Accessed on May 6, 2012

7.Meininger, Kathryn, “Medications That Treat Staph Infections,” LIVESTRONG.COM. Accessed May 6, 2012.

8.[http://www.medicinenet.com/leptospirosis/article.htm Cunha, John P, “Leptospirosis Symptoms, Vaccine, Treatment, Prevention, Diagnosis and Prognosis Information,” MedicineNet. Accessed on May 6, 2012.]

9.“Lyme Disease: Causes, Incidence, and Risk Factors“ US National Library of Medicine. Accessed May 6, 2012

10. Balentine, Jerry, “Typhoid Fever: History, Treatment, Causes, Symptoms, Vaccine ” MedicineNet. Accessed May 6, 2012

11.“Bacteria Genomes - CLOSTRIDIUM PERFRINGENS”. Accessed May 6, 2012

12. “Necrotizing Soft Tissue Infection: Causes, Incidence, and Risk Factors” US National Library of Medicine, November 18 2000. Accessed May 6, 2012.

13.Murray, John F, “A Century of Tuberculosis", American Journal of Respiratory and Critical Care Medicine, March 20, 2004. Accessed May 4 2012.

14."Penicillin- like Antibiotics" Daily Science. May 4, 2012.

15.James, Christopher W. "Cross- reactivity of Beta- actam Antibiotics" US National Library of Medicine. Accessed May 7, 2012

16. Brayer, Toni "Life Saving Antibiotics Losing Power Due to Resistant Germs". Everything Health. Accessed May 7, 2012.

Edited by Shane Carrera, Oliver Van Zant, Henry Van Zant, and Nancy Walker

students of Rachel Larsen in Bio 083 at Bowdoin College [1]