by Alexandra Cantley
figures by Joy Jiao and Shannon McArdel

Over the last several years, antibiotic resistance has gripped the attention of the public. Recently, newspapers have alerted us to a “superbug” in China and detailed the struggles of Daniel Fells, a Giants team member who is facing surgery for a persistent MRSA infection [1,2]. Yet, a recent survey conducted by the World Health Organization (WHO) revealed that while 2/3 of people surveyed were aware that antibiotic resistance poses a serious threat, most of these people were uncertain as to how antibiotic resistance works, who it affects and why it is a problem [3]. As antibiotic resistance is an issue that affects every population in every country in the world, finding clarity on these questions is essential to decreasing the spread of these rapidly evolving pathogens.

The discovery of penicillin

Prior to 1950, afflictions caused by bacteria, such as pneumonia or wound infection, were the leading causes of death in the general population.  In 1928, Alexander Fleming made his mark on modern medicine when he isolated the first antibiotic from Penicillium, a common fungus.  By the 1940s penicillin was already widely used and previously fatal infections could be effectively cured by this miracle drug. However, penicillin’s reign as a life-saving treatment was short lived; by 1947 scientists had already identified bacteria that could resist the toxic effects of this molecule.

Unfortunately, this rapid emergence of penicillin-resistance has proven to be a trend. Since the 1940s, many new types of antibiotics have been discovered and approved in the clinic; however, resistant bacteria often emerge in as few as 5 years after an antibiotic’s introduction [4,5]. Today we regularly grapple with bacteria that are extremely resistant to multiple types of antibiotics.  These bacteria are commonly referred to as “superbugs” [6,7].

Antibiotics and resistance: an overview

“Antibiotic” is a catch-all for any kind of molecule that is toxic to living microorganisms (including bacteria or fungi). This overarching term is often used interchangeably with “antibacterials” – or drugs that specifically kill bacteria or inhibit bacterial growth.  Since the success of penicillin, many different types of antibiotics have been discovered from natural sources or developed synthetically in the lab. Each of these types of antibiotics binds to distinct proteins in the bacterial cell in order to disrupt key cellular processes, and because of their diverse activities they display widely varied toxicity against different types of bacteria. Figure 1 describes the three main ways antibiotics work [5, 6].

Despite the many ways in which antibiotics function, bacteria have managed to develop strategies to counteract these lethal effects. So how do antibiotic resistance bacteria manage to evade or prevent the lethal activities of these drugs? Surprisingly, the approach is pretty simple (Figure 2):

Remove the antibiotic.  Bacteria produce transport systems, called efflux pumps that actively remove noxious substances from the cell.  These pumps are a more general strategy of resistance – they do not recognize just one type of antibiotic but perform a broad sweep of toxic molecules in the cell [4,5].

Destroy the antibiotic: The first bacteria discovered to be resistant to penicillin was found to produce a protein that could destroy an essential part of the drug molecule, rendering the drug ineffective.

Bypass the inhibited protein:  As depicted in Figure 1, antibiotics can prevent a bacterial protein from performing tasks essential to cell survival; in this form of resistance the bacteria find alternate ways to perform these tasks.  Bacteria achieve this type of resistance by producing redundant proteins, or back-ups, that fulfill the same responsibilities of the inhibited protein. This bypass strategy is employed by Methicillin Resistant Staphyloccocus aureus (MRSA), one of the most infamous “superbugs” [8].

How does bacterial resistance arise?

Bacteria have been producing antibacterial molecules for long before humans existed.  In the soil, which is teaming with microorganisms, the production of antibiotics helps bacteria kill off other bacteria or fungi that are competing for common resources. Some ecologists liken these antagonistic interactions to “chemical warfare” [9]. Resistance genes evolve through the accumulation of mutations that allow bacteria to survive in the presence of toxic molecules. When bacteria divide and multiply, the machinery controlling DNA replication can make mistakes. These mistakes, or “mutations,” often negatively affect the survival of the organism, but sometimes a mutation will occur that has a positive effect on a bacterium’s survival. In the presence of an antibiotic, a mutation rendering a bacterium resistant to this toxic substance is a huge advantage; because bacteria grow and divide rapidly, it doesn’t take long for a population of these resistant offspring to dominate the population (Figure 3).  With this in mind, it is unsurprising that for most of our antibiotics, which come from natural sources (like bacteria from the soil), a resistance gene already exists. In fact, the gene conferring resistance to penicillin was discovered before penicillin even became an approved drug [4].

While antibacterial resistance has always existed, it is the rampant use of antibiotics by humans that fuel the epidemic we are facing today.  How have humans contributed to this problem? The main culprit is overuse.  Back when we were blissfully unaware that resistance would become a problem, antibacterials were frequently recommended before determining the infectious agent was even bacterial (as you may have heard, antibiotics do not work against viruses).  As mentioned above, the presence of an antibiotic will favor mutations that render the bacteria resistant to the drug.  The overuse of antibiotics does exactly that; bombarding the environment with antibiotics gives bacteria the chance to evolve mutations that favor their survival in the presence of the these drugs, whereas bacteria that have never been exposed to an antibiotic are less likely to already harbor strategies for resistance.

The incorrect administration of antibiotics also promotes the survival of resistant bacteria.  For example, many patients will choose to cut their antibiotic regiment short after their infection begins to subside. Taking an incomplete dose of an antibiotic not only allows slightly resistant bacteria to persist in the patient, it also increases the likelihood that a re-emerging infection will now be resistant to the previously administered antibiotic.  In other words, the infection-causing bacteria have now been exposed to the drug, giving them the opportunity to generate mutations that may result in resistance to the prescribed antibiotic.

Antibiotics are also employed excessively in agriculture and farming. While in theory these drugs are used to treat sick animals, they are often utilized as a preventative measure.  Additionally, it has been shown that antibiotics can increase the size (and thus value) of livestock, giving farmers even further incentive to over-utilize them [5].  Much like the over-prescription of antibiotics for human disease, these practices further increase the abundance of these molecules in the environment, giving bacteria the opportunity to evolve new ways to evade their toxicity.

What is being done to combat antibiotic resistance?

The most obvious way to combat antibiotic resistance is to minimize how much we use antibiotics.  Doctors and clinicians have become more wary of prescribing antibiotics for infections that could potentially resolve themselves, and programs like “Get Smart”, run by the CDC, aim to increase awareness in patients about when and how antibiotics should be administered [10].

The overuse of antibiotics in the meat industry has also garnered much attention and the FDA has now recommends that antibiotic use be reserved for sick animals only.  As of now these measures are on a voluntary basis, but many believe that stricter regulations must be enacted to truly compel change [11].

Both academic labs and biotech companies are exploring better diagnostic tools for detecting antibiotic resistant bacteria [12].  Generally, resistant infections are detected through trial and error; doctors will administer one antibiotic and then switch to another if the bacteria do not respond.  Not only does this approach waste time, it can also have unexpected negative effects [13]. More efficient methods of determining bacterial sensitivity to antibiotics could greatly enhance treatment for infections, and help contain potential outbreaks.

Researchers are also investigating new strategies to kill multi-drug resistant bacteria.  One approach is to try and find new antibiotics that target different processes in bacteria.  Last year researchers at Northeastern reported the discovery of a new antibiotic, Teixobactin, which is effective against Mycobacterium tuberculosis and MRSA. This drug works differently than any antibiotic currently in use, and while research on Teixobactin is still in its infant stages, bacteria resistant to this antibiotic have yet to be discovered [14].

Similarly some researchers are interested in targeting the strategy of resistance itself. Augmentin, a mix of amoxicillin and a second molecule that blocks the bacterial resistance mechanism to amoxicillin, is a successful example of this strategy.  Efflux pumps that remove antibiotics, the broadest and most utilized resistance mechanism, are also intriguing targets for these types of combination therapies [4].

Since the release of the WHO survey, and in the wake of multiple news stories about “superbugs,” US funding sources have announced a plan to increase federal spending on antibiotic research by more than 50%. This money could help prevent outbreaks by supporting improved infrastructure and hygiene practices in clinics and hospitals. Additionally, these grants will fund academic research on antibiotic resistance through allocation of grants by the National Institute of Health [15].  This burst in funding could have a major impact on research into the previously described approaches to combat antibiotic resistance.

While the pursuit of novel treatments and diagnostics for antibiotic resistant infections will remain essential research focuses in biotech and academia, adjusting human behavior and attitudes towards antibiotics is likely the most significant hurdle we face.  The survey mentioned at the beginning of this article made it abundantly clear that there is a serious lack of communication among clinicians, researchers, and the general public. Since the results of this survey were released, the WHO has launched a global campaign to improve education on the dangers and causes of antibiotic resistance [3]. It is likely that, in the next several years, more campaigns and educational programs like this will follow.

Of course, antibiotic resistance is not a problem with a simple solution – as long as antibiotics are still in the environment, bacteria will find a way to evade their toxic effects. However, raising awareness about how humans have contributed to this world health crisis, and examining what we can do to slow its progression, will be our best chance at defeating, or at least slowing down, these “superbugs.”

Alexandra Cantley is a 5^th year graduate student in the Chemical Biology Program at Harvard University.  Her research in the Clardy Lab focuses on the exploration of chemical interactions between bacteria and other microorganisms.

References

[1] Perez, AJ., “Giants TE Daniel Fells to have 10th surgery to treat MRSA” USA Today, 7 Dec. 2015
http://www.usatoday.com/story/sports/nfl/giants/2015/12/07/daniel-fells-mrsa-surgery-new-york-giants-nfl/76915784/

[2] Kelland, K., “New “Superbug” Gene Found in Animals and People in China” Scientific American, 19 Nov. 2015
http://www.scientificamerican.com/article/new-superbug-gene-found-in-animals-and-people-in-china/

[3] “WHO multi-country survey reveals widespread public misunderstanding about antibiotic resistance” The World Health Organization, www.who.int 16 Nov. 2015
http://www.who.int/mediacentre/news/releases/2015/antibiotic-resistance/en/

[4] Davies, J. & Davies, D., “Origins and Evolution of Antibiotic Resistance” Microbiology & Molecular Biology Reviews (2010).
http://mmbr.asm.org/content/74/3/417/

[5] Smith, R. et al., “Antibiotic Resistance: A Primer and Call to Action” Health Communication (2015).
http://www.ncbi.nlm.nih.gov/pubmed/25121990/

[6] Antibiotic/Antimicrobial Resistance, Centers for Disease Control and Prevention, www.cdc.gov
http://www.cdc.gov/drugresistance/

[7] Groopman, J. “Superbugs”, The New Yorker (2008)
http://www.newyorker.com/magazine/2008/08/11/superbugs

[8] Chamber, H.F., & DeLeo, F.R., “Waves of resistance: Staphyloccocus in the antibiotic era” Nature Reviews Microbiology (2009).
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2871281/

[9] Wade, N., “Researchers Find Antibiotic Resistance in Ancient DNA” The New York Times, 31 Aug. 2011
http://www.nytimes.com/2011/09/01/science/01gene.html

[10] “Get Smart” Centers for Disease Control and Prevention (CDC)

[11] “FDA Regulation to Help Ensure Judicious Use of Antibiotics in Food-Producing Animals” U.S. Food and Drug Administration, www.fda.gov 2 Jun. 2015
http://www.fda.gov/AnimalVeterinary/NewsEvents/CVMUpdates/ucm448620.htm

[12] Buguliskis, J., “The fight against antibiotic resistance has a new ally” Genetic Engineering & Biotechnology News Dec. 14, 2015
http://www.genengnews.com/insight-and-intelligence/the-fight-against-antibiotic-resistance-has-a-new-ally/77900580/

[13] Winter, G., “Beta-lactam antibiotics can make MRSA infection worse” The Pharmaceutical Journal Nov 12, 2015
http://www.pharmaceutical-journal.com/news-and-analysis/news/beta-lactam-antibiotics-can-make-mrsa-infection-worse/20200058.article

[14] Ledford, H, “Promising antibiotic discovered in microbial ‘dark matter’” Nature (2015)
http://www.nature.com/news/promising-antibiotic-discovered-in-microbial-dark-matter-1.16675

[15] Sun, L., “Fight against superbugs gets dramatic funding boost under congressional budget plan” The Washington Post Dec. 17, 2015
https://www.washingtonpost.com/news/to-your-health/wp/2015/12/17/fight-against-superbugs-gets-dramatic-funding-boost-under-spending-plan/

Cover Image is from the NIAID Flickr and is licensed by Creative Commons Attribution 2.0 Generic.