Hooray for Penicillin (And How We're Shooting Ourselves in the Foot for the Future)

Introduction

We’ve all seen the headlines: “New ‘super bug’ resistant to antibiotics” , “Student dies of unbeatable infection”, “Deadly infection kills patients in hospitals at alarming rate”. They all point to a disturbing new reality: the effectiveness of antibiotics has severely decreased as the bacteria they once so easily destroyed develop resistance. What is the basis for this claim? Why are our antibiotics no longer functional? How do they work to begin with? This paper will explore all of the above topics with a focus on penicillin, the first antibiotic to significantly alter the scales in our fight against bacterial infections. We will then discuss how bacteria develop and combat antibiotics, and how an overuse of antibiotics leads to the problem we face today: a human population defenseless against an ever-growing number of strains of resistant bacteria.

The Development of the First Commercial Antibiotic

Antibiotics are chemical substances created by microorganisms that can kill or inhibit the growth of other microorganisms (3). One of the first known uses of antibiotics was nearly 2,500 years ago by the Chinese, who discovered that applying a moldy curd of soybeans to wounds helped fight off infections. However, it was not until significant strides made by contemporary scientists, such as Anton van Leeuwenhoek (discovered of bacteria in 1676) and Louis Pasteur (developed germ theory of disease) that humanity had any idea about why the molds were working.

In 1928, Alexander Fleming was doing research at St. Mary’s Hospital in London on cultures of staphylococcus aureus in order to test his theory that his own nasal mucus had antibacterial effects. Fleming accidentally left one of his petri dishes with a culture of staphylococcus aureus uncovered for a few weeks while on Christmas holiday. Upon his return, he noticed that this petri dish had been invaded by a yellow green patch of mold, which Fleming identified as Penicillin notatum. Most important was that in the area immediately around the mold, the bacteria had been cleared away. Fleming let the mold continue to grow; as it spread, staphylococcus aureus bacteria kept disappearing. Fleming guessed that there was an active ingredient or secretion by the mold which was able to kill of the bacteria, which he was able to isolate; this he named penicillin. However, Fleming did not believe that penicillin would have a real world application as the substance was very unstable and did not always work (3). Fleming published his last paper on penicillin in 1931 (3), though he kept a bunch of old samples around for other scientists to use (2). It was Howard Florey and Ernst Boris Chain who, with funds from the Rockefeller Foundation and one of Fleming’s old samples, were able to extract and purify penicillin from the mold and inject it into mice with streptococcus, thereby inventing a drug which saved millions of lives in World War II (2).

How Antibiotics Work

Like all antibiotics, penicillin acts by attacking a crucial life process of a bacterium, usually by inhibiting new growth while a cell is dividing and synthesizing new material. To understand how penicillin works in particular, we must first understand a little bit about the life and anatomy of a bacterium. Bacterium reproduce by a process called binary fission, in which the original bacterium splits into two daughter cells. At the beginning of this process, the cell expands and acquires adenosine triphosphate (ATP) a chemical compound used for energy. When it has acquired sufficient ATP it begins replicating the inner organelles and DNA (genetic instructions for recreating the organism). Once this process is complete, the cell reaches the point where a new cell wall is created and the cell finally divides.

Like all prokaryotic cells, the bacterium is bounded by a cell wall. For bacteria, this wall is constructed of polysaccharide chains (a type of carbohydrate, which is a type of macromolecule) linked together by peptide cross links (special type of bond formed between two molecules). In the creation of the new cell wall, the enzyme transpeptidase is needed to join these different parts together. What penicillin does is block the action of the enzyme, as the enzyme locks onto the penicillin and is unable to help synthesize the cell wall.

Inside a cell, the concentration of chemicals is much greater than what is outside the cell, resulting in a hypotonic state, where there is a low concentration of solute relative to the solution inside the water (solute being whatever is not water) which is maintained by the cell wall. If the cell wall is weak or parts of it are missing, water (or whatever substance the cell is floating in) will rush inside the cell and the cell will burst due to osmotic pressure. So, when a bacterium divides in the presence of penicillin, it is unable to form new cell wall and bursts. Note that penicillin does not act on existing cell walls, but only those which are in the process of being created. Also, penicillin does not work on viruses because viruses do not have cell walls.

Why Are Antibiotics Not as Effective as Before?

There has recently been a lot of talk in the news of Methicillin-resistant Staphylococcus aureus, also known as MRSA. This bacteria has evolved to counter the penicillin with its own enzyme (named penicillinase), which latches onto the penicillin and prevents it from binding with the transpeptidase. MRSA and other antibiotic resistant bacteria acquired this trait through exposure to antibiotics. This exposure results in the creation and selection of new, resistant strains of bacteria which develop through a process similar to natural selection (3). For example: when a strain of bacteria enters your body, it divides itself many, many times, and on occasion it mutates. Sometimes these mutations allow the bacteria to resist antibiotics. Now if we attack the bacteria with antibiotics, all but the few mutated bacteria will die, leaving the mutated bacteria to occupy the host body and spread to other host bodies. This natural selection increases the number of resistant bacteria, which then propagate themselves through other means. These bacteria may then help other bacteria develop resistance by sharing genes within and across bacterial species. This can occur through three different processes: conjugation, transduction, and transformation (6). Conjugation is a bit like microbial sex: DNA crosses through a sex pilus (tube which projects from the cell wall of a bacterium) as cells make direct contact (6). In transformation, the bacterium picks up DNA left behind from another cell in the environment, which can then be recombined with the existing DNA within the bacterium, resulting in a new genotype and new strain of bacterium (6). In transduction, a virus is responsible for carrying DNA between two mating bacteria (6). The disturbing results of these methods are that bacteria are able to pass on genes not only without reproducing and within the same strain and species, but they also pass these genes onto strains of other species. That is, Streptococcus aureus could pass its genes on to Shigella or Mycobacterium tuberculosis (6), two types of bacterium which are responsible for dysentery and most cases of tuberculosis, respectively. This makes combating bacteria much more difficult, because even if a particular strain has not been introduced to a certain antibiotic, it is still capable of developing a resistance to it. Before we know it, the majority of a population of a certain kind of bacteria become resistant and our drugs don’t work.

What Can We Do About Bacteria Resistance?

The next question to ask ourselves is whether we can adapt to this change, and the answer is yes. In order to combat drug resistant bacteria, it is possible to create “novel analog drugs”, that is, new varieties of antibiotics which are slightly different than their originals yet achieve the same function (9). These drugs are able to avoid the bacterial enzymes which could inhibit the original version of the drug. An example of a novel analog drug is minocycline, which is a derivation of tetracycline. Instead of developing new drugs, it is also possible to pair an existing drug with an acid that inhibits the bacterial enzymes which try to inhibit the drug (9). For example, b-lactamase, an enzyme found in some bacteria, is able to resist amoxicillin, a synthetic type of penicillin. However, when amoxicillin is combined with clavulanic acid, the clavulanic acid destroys the b-lactamase (9), allowing the amoxicillin to act upon the cell wall of dividing bacteria and destroy them. There is also ongoing research to develop antibiotics which attack the bacteria with new mechanisms (9). For example, in existence there are already drugs which attack cell walls in different areas than penicillin (glycopeptides, e.g. vanomycin), those that block DNA synthesis (quinolones), and those that inhibit protein synthesis (tetracyclines), though there are many others beyond these varieties (10).

The thing is, bacterial resistance wouldn’t be such a problem if we just learned how to prescribe antibiotics correctly. In our “give me it instantly” society, patients often pressure doctors to prescribe antibiotics for them, even when the cause happens to be a virus, not a bacteria (7). Doctors also liberally give out antibiotics for sinusitis and ear infections; for example, there were 23.6 million antibiotic prescriptions for antibiotics in 1992 (7). This misuse and abuse of antibiotics is creating problems for us because bacteria are defeating the antibiotics before new ones are created. Drugs that were once life savers, such as natural penicillins, have become entirely useless. Part of this is the joint fault of doctors and consumers, but also on pharmaceutical companies, who are the ones who have been doing most, if not all of the research (11). Unfortunately, for these companies, there is no real financial incentive to produce antibiotics. Developing antibiotics is a risky business venture for pharmaceutical companies, who, under recent financial pressure, feel that the only way to survive is to get bigger (11). Instead, of developing antibiotics more money is being spent on “lifestyle” drugs (drugs for depression, osteoporosis, erectile dysfunction) than on antibiotics, because antibiotics take a really long time to research and put on the market (8 to 10 years) and a lot of money (excess of $500 million per drug) (11). The greatest problem for pharmaceutical companies concerning antibiotics is that these costs will not be recouped. Only a certain segment of the population (elderly, children, those in hospitals, etc) will take the drug and only for relatively short period of time, whereas depression drugs can be taken for a period of several years to a lifetime. There is the risk that the antibiotic will become useless in five years as the bacteria develop a resistance to it (11).

Conclusion

If we want to maintain the miracles of the “wonder drugs”, we need to stay ahead of the game and take responsibility for our mistakes by controlling how often we use antibiotics and when. The best way to do this would be to raise public awareness. Instead of getting the media to focus on the horrors of MRSA and how we must be more cleanly in our schools in our hospitals, we need to get them to focus on our abuse and misuse and abuse of antibiotics. Cleanliness, while an important issue, is secondary, because cleanliness alone will not stop bacteria from mutating more often, and thereby developing resistance to antibiotics at high rates. However, a change in the way we use antibiotics will help us maintain the effectiveness of the drugs we have so that research can catch up before these drugs become obsolete. We also need to provide incentives for pharmaceutical companies to research new drugs and/or move research into government hands. We do not want to be in a situation where we are stuck with obsolete drugs and super bacteria. Such a situation would be reminiscent, if not almost identical on the patient end of things, to pre-antibiotic days. We would probably see an increased mortality rate among all people, with a possible reduction in average lifespan. Also, specific groups would be more at risk than the average Joe, such as those in prisons, those with AIDS, those with illegal drug addictions, and anyone else whose immune system is still developing or severely comprised, such as in infants and in the elderly (9), not to mention increased mortality rates among those in third world countries where susceptibility to such diseases as E. Coli is prevalent. What is the best defense for the average consumer? Maintaining one’s personal hygiene, no matter the situation. This means going to hospitals which maintain strict hygiene procedures and using antiseptic cleansing sprays on home surfaces. Mom was right: wash your hands!

References:

1) Ho, Dr. David. "The TIME 100: Alexander Fleming." TIME. <http://www.time.com/time/time100/scientist/profile/fleming.html>.
2) How Penicillin Works. Dir. Andy. Perf. Andy. YouTube. <http://www.youtube.com/watch?v=AjYOGJrruoU>.
3) Brown, John C. "What the Heck is Penicillin?" Department of Molecular Biosciences. July 2001. University of Kansas. <http://people.ku.edu/~jbrown/penicillin.html>.
4) Moran, Professor Larry. “How Penicillin Works to Kill Bacteria.” [Weblog entry.] Sandwalk: Strolling with a Skeptical Biochemist.
<http://sandwalk.blogspot.com/2007/06/how-penicillin-works-to-kill-bacteria.html>.
5) Moran, Professor Larry. “Penicillin Resistance to Bacteria: Before 1960.” [Weblog entry.] Sandwalk: Strolling with a Skeptical Biochemist.
<http://sandwalk.blogspot.com/2007/06/penicillin-resistance-in-bacteria.html>
6) Todar, Kenneth, P.h.D. “Antimicrobial resistance.” Textbook of Bacteriology. University of Wisconsin-Madison. <http://textbookofbacteriology.net/resantimicrobial.html>.
7) Lewis, Ricki, P.h.D. "The Rise of Antibiotic-Resistance." Food and Drug Adminstration Home Page. Sept. 1995. FDA. <http://www.fda.gov/fdac/features/795_antibio.html>.
8) McCaughey, Betsy. "Coming Clean." New York Times 6 June 2005. <http://www.nytimes.com/2005/06/06/opinion/06mccaughey.html?_r=1&n=Top/News/Health/Diseases,%20Conditions,%20and%20Health%20Topics/Hospitals&oref=slogin>.
9) Silver, L L., and K A. Bostian. "Discovery and Development of New Antibiotics: the Problem of Antibiotic Resistance." Antimicrob Agents Chemother 37 (1993): 377-383. PubMed. <http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=187680>.
10) "How Antibiotics Work--the Mechanism of Action." Alliance for the Prudent Use of Antibiotics. 1999. <http://www.tufts.edu/med/apua/Miscellaneous/mechanisms.html>.
11) Charles, Patrick G., and M L. Grayson. "The Dearth of New Antibiotic Development: Why We Should Be Worried and What We Can Do About It." The Medical Journal of Australia 181 (2004): 549-553. <http://www.mja.com.au/public/issues/181_10_151104/cha10412_fm.html>.