On Monday, Sept 3rd, 1928, Dr. Alexander Fleming, a renowned Scottish scientist, returned to his London laboratory after a family vacation, and made a chance discovery that would revolutionize medicine and change the course of history.

Fleming had been studying staphylococci, a common variety of skin-dwelling bacteria that frequently infect wounds. During World War I, Fleming had witnessed firsthand how even minor battlefield wounds became deadly if infected. At the time, the only substances known to kill bacteria were also toxic to humans. Keenly aware of the need for safe anti-bacterial drugs, Fleming began searching for such compounds after the war. On that Monday morning, as he was sorting through Petri dishes of Staphylococci he had left on his laboratory bench before going on vacation, Fleming noticed one that had become contaminated with mold. Fungal contamination was not particularly unusual, but what was remarkable was that all of the bacterial colonies immediately surrounding the mold had died. Fleming subsequently identified the mold as belonging to the genus Penicillium and found that it naturally produced a substance that was lethal not only to staphylococci, but to a wide range of bacteria including those responsible for diseases like pneumonia, gonorrhea, meningitis, and scarlet fever. He named the miracle compound “penicillin.” Fleming’s serendipitous discovery marked the beginning of the modern medical era of antibiotics, played a critical role in the Allies’ victory during World War II, and has likely saved more lives than most other medical advances in history.

How antibiotics kill bacteria

Since the discovery of penicillin, an extensive arsenal of highly effective antibiotics has been derived from both natural and synthetic sources. In the process, we’ve learned much about the way antibiotics kill bacteria. Unlike humans, plants, and animals, which are made up of trillions of cells, bacteria are single celled organisms. Most antibiotics target basic biological processes necessary for the growth and survival of bacterial cells. Quinolones for instance (e.g. ciprofloxacin), are a class of antibiotics that tamper with the cellular apparatus responsible for unwinding and rewinding DNA, which is normally packed away into tight coils. If the DNA can’t be unwound, it cannot be replicated or repaired, and its genes cannot be read to produce new cellular components. Quinolone-treated bacteria can thus no longer divide or sustain themselves, and die. Other classes of antibiotics, such as beta-lactams (e.g. penicillin), operate by blocking the construction and maintenance of the bacterial cell wall, a protective mesh made of sugars and proteins. Beta-lactams target the machinery necessary to fuse together components of the cell wall, such that bacteria treated with these antibiotics become fragile and eventually burst [1]. While bacterial cells are in many ways similar to the cells in our body, the machinery our cells employ is different enough that most antibiotics are not toxic to us.

The rise of antibiotic resistant superbugs

Less than 20 years after Fleming’s discovery, physicians realized something was wrong. By then, penicillin was being used in hospitals to treat many different diseases with unprecedented success. In some patients, however, doctors noticed that staphylococcal infections were no longer clearing up after penicillin treatment. The bacteria were becoming “resistant”. Scientists discovered that these resistant bacteria produce a protein, penicillinase, which specifically destroys penicillin before it can harm the bacteria. With time and the increasing use of the antibiotic, the number of drug-resistant cases soared.  In 1946, Fleming, who had himself characterized several staphylococcal isolates that were insensitive to penicillin, wrote “there is probably no chemotherapeutic drug to which in suitable circumstances the bacteria cannot react by in some way acquiring ‘fastness’ [resistance],” [2] a prescient statement that today resonates more ominously than ever.  Indeed, despite the vast expansion of our antibiotic arsenal, a compound to which bacteria do not eventually become resistant remains to be identified.

Over the years, the problem has compounded with the world-wide appearance of ‘superbugs’, bacteria resistant to more than one, and sometimes every available drug. Diseases that could previously be treated are becoming more and more difficult to control, and some have become incurable. Some of the most infamous of these superbugs include drug resistant E. coli, XDRTB (extensively drug resistant Mycobacterium tuberculosis), and Pseudomonas aeruginosa, a bacterium that causes disease in people with weakened immune systems or cystic fibrosis patients. The center for diseae control estimates that MRSA (Methicillin-resistant Staphylococcus aureus), a highly resistant version of a common skin dwelling organism, lives on the skin of 2% of the population in the US and is a major cause of life-threatening hospital-acquired infection.

Bacterial resistance arises through the simple process of natural selection. Bacteria divide rapidly, but DNA replication is imperfect. Once in a while, errors occur when the genome is copied, and these errors give rise to ‘mutant’ bacterium. If by chance, a mutant can reproduce more successfully than its non-mutant peers, it will eventually out-compete them. In the presence of antibiotics, while most bacteria are killed, a small number of resistant mutants may survive and take over. For instance, a small alteration in the machinery that unwinds bacterial DNA can confer resistance to quinolones, the drugs that interfere with this process. Similarly, some bacteria have evolved special pumps to actively expel drugs that have breached the cell wall. Not only do bacteria develop sophisticated ways of dealing with drugs, but they can also share resistance genes with other bacteria, and even with bacteria of other species. Indeed, some bacterial resistance genes are on loops of DNA (called plasmids) that are not part of the bacterial genome and can be transferred from bacterium to bacterium in a process called “conjugation”. Genes can also be transferred by viruses that infect multiple bacteria or through uptake of DNA from sources such as dead bacteria. Because bacteria can share genetic information, the harmless bacteria that live in our bodies can serve as a reservoir of resistance genes that can then be shared with more disease-causing organisms. Studies have shown that antibiotic resistant, non-harmful bacteria can persist in our bodies for months or even years after antibiotic treatments, making them an important source of resistance factors for disease causing bacteria [3].

Although the development of antibiotic resistance is an inevitable consequence of microbial adaptation, the widespread overuse and misuse of antibiotics in medicine is in large part to blame for the rapid rise of superbugs. In addition, the non-therapeutic use of antibiotics in animals for human consumption (usually to enhance growth) is of great concern because sub-clinical levels of antibiotics are particularly efficient at driving the selection of resistant bacteria. Indeed, low amounts of antibiotics, while non-lethal, can trigger bacterial stress responses that, among other things, cause an increase in the frequency of errors (or “mutations”) that occur during DNA replication. This means that bacteria subjected to low levels of antibiotics can evolve resistance traits faster. Unfortunately, in many countries including the US, nearly all clinically essential classes of antibiotics are actively used as food additives for cattle, swine and poultry, despite a 1997 World Health Organization recommendation to restrict this practice, which is leading to the spread of resistant organisms in the environment [4].

The way forward

As the rise of antibiotic resistance threatens health care world wide, new ways to fight bacterial infection are being intensely investigated. Scientists are searching for new antimicrobials by brute force: gigantic assortments of tens of thousands of chemical compounds are being tested for the ability to kill bacteria or interfere with their capacity to cause disease. Alternatives to antibiotic compounds are also being explored. In particular, bacteriophage therapy (or “phage” therapy), a method that was being investigated before the discovery of penicillin and largely abandoned thereafter, is gaining attention [5]. Phage therapy relies on the use of viruses that infect and kill certain bacteria very specifically, and, while bacteria could still develop resistance to phage, phage treatment is hypothesized to have very few side effects since the viruses can only attack their target bacteria. Unfortunately, the discovery of new methods to treat bacterial infections lags behind the development of anti-microbial resistance, and new therapies will likely face the same issues once they are introduced, making responsible use of currently available and future drugs an imperative.

Nadia Cohen is a recent graduate of the Immunology PhD program at Harvard University, Division of Medical Science.

Useful Resource:

Alliance for the Prudent Use of Antibiotics (http://www.tufts.edu/med/apua/)

References:

[1] Kohanski, M.A., Dwyer, D.J & Collins, J.J. How antibiotics kill bacteria. Nature Reviews Microbiology; 8:423; 2010.

[2] Fleming, A. Chemotherapy, Yesterday, Today and Tomorrow. Linacre lecture, Cambridge University press; 1946.

[3] Levy, S.B. & Marshall, B. Antibacterial resistance worldwide: causes, challenges and responses. Nature Medicine Supplement; 10(12):S122; 2004.

[4] Silbergeld, E.K., Graham, J. & Price, L.B. Industrial food animal production, antimicrobial resistance, and human health. Annual Reviews in Public Health; 29:151;2008.

[5] Gross, M. Revived interest in bacteriophages. Current Biology, 21(8):R267; 2011.

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