What is antibiotic resistance and Why does it matter?

Our world was a very different place before 1928, when Sir Alexander Fleming discovered the very first antibiotic – penicillin. Weaponless, we as humans were much more vulnerable to the microscopic pathogens around us.

In order to appreciate how far we’ve come, consider that a single bacterial species Streptococcus pyogenes alone used to cause half of all post-birth deaths. Infected cuts in the skin, or mild throat infections would become very serious very quickly without medicine, and were enough to defeat the human body. Today, there is an estimated 700 million new infections worldwide each year by this bacterium, yet we are able to manage it.

Sure enough, between 1944 and 1972 human life expectancy jumped by eight years – an increase largely credited to the introduction of antibiotics. Thanks to these new drugs, diseases that once used to be lethal now had a cure, having an enormous impact on the welfare of individuals and societies. Antibiotics had revolutionized medicine.

However, enough time has passed for bacteria to evolve and start finding ways to get around antibiotics, rendering some of the treatments useless. Unicellular organisms are outsmarting doctors and scientists, and we can only blame ourselves. Yes, mutations i.e. changes in an organism’s genetic makeup are slow, naturally occurring processes of evolution, and these processes will be discussed in more detail later. However, the inappropriate use of antibiotics in clinical settings as well as in livestock has created selective pressure, driving the emergence of new multidrug-resistant strains. Because of this erroneous practice, antibiotics are becoming obsolete much faster than they have to.

A post-antibiotic era means, in effect, an end to modern medicine as we know it. Things as common as strep throat or a child’s scratched knee could once again kill.
– Dr Margaret Chan, Director-General of the World Health Organisation

In order to understand how and why antibiotics are losing their power, it is important to understand how antibiotics work in the first place, followed by what mechanisms bacteria use to block their actions. Antibiotics take advantage of the structural and functional differences between human and bacterial cells, of which there are quite a few. On top of being much smaller and more primitive than human cells, one distinct feature is the presence of a cell wall that provides the bacterium with structural protection. When a bacterial cell divides in two, it has to synthesise more of it, enough for both of its daughter cells. Penicillins and Glycopeptides are antibiotic agents that inhibit cell wall synthesis, thus stopping bacteria from dividing. This example also illustrates how antibiotics can specifically target bacteria without doing harm to host cells, and can thus be safely administered at relatively high doses. In order to kill bacterial cells, most antibiotics target various components of the so-called “information processing” machinery of the cell. This term refers to a network of all the cellular components and biochemical reactions that utilize the genetic information encoded in the cell’s DNA. Information contained in DNA is used to synthesize all proteins and molecules essential for life, thus bringing about all of the organism’s structures and functions. For example, antibiotics such as tetracyclins and aminoglycosides inhibit protein synthesis by binding to the bacterial ribosomes, whilst fluoroquinolones inhibit bacterial DNA synthesis. The take-home message here is that these processes are absolutely essential for life, and they are structurally different to the equivalent machinery we humans have in our cells, thus making them great drug targets.

Resistant bacteria have several possible, sneaky mechanisms in which they evade antibiotics. Some have become less permeable to drugs so fewer molecules get inside the cell, and some even have efflux pumps that actively sweep the drug out of the cell. Some bacteria produce enzymes that attack the very chemical structure of antibiotics, such as beta-lactamases that neutralize penicillins. In addition, the cellular targets of the drug can change shape over time, so that the drug no longer recognizes them. But how does this happen – how do bacteria acquire these new “powers”?

Over time, the genetic makeup of an organism can change in the slightest through accumulating mutations. When a dividing cell makes a copy of its DNA, an error might occur, and a single letter of the genetic code, for instance, could be replaced with another one. This mutation can have different effects on that gene’s function, depending on what was inserted/deleted/substituted and where. The mutation can be neutral and have no effect on the protein at all, or it can be detrimental to that protein’s function. In some instances the change can be beneficial, slightly altering the protein’s function to the organism’s selective advantage. For example, a mutation could occur in a cell membrane protein that an antibiotic recognizes. Perhaps this protein has changed shape in such a way that the antibiotics can no longer bind to it.

Bacteria are more error prone copiers of their DNA, and don’t have such elaborate DNA code proofreading mechanisms as humans do, so mutations occur more frequently. However, only one in 1 000 000 000 bacteria will acquire antibiotic resistance through a mutation. Even though the occurrence of mutations is very rare, the exponential growth rate of bacteria ensures that resistance quickly arises in a population. This phenomenon is called vertical gene transfer, and is strictly governed by Darwinian evolution by the principles of natural selection. When an antibiotic (a selective pressure) is present, other bacteria die, and the ones with resistance are able to grow and flourish (See Figure 1 below.)

Figure 1: The effect of selective antibiotic pressure in bacteria. Adapted from Mulvey & Simor (2009)

Mutations lead to slow, random and gradual changes in the DNA, but bacteria utilize a different method to further speed up their evolution. Bacteria reproduce asexually, i.e. they literally split themselves in half, essentially creating clones of themselves with identical genetic makeup. But they have the amazing ability to exchange genetic material with other bacteria via “horizontal gene transfer”. This enables bacteria to send and receive small circular packages of DNA called plasmids between members of the same, or even different bacterial species. These genes are often antibiotic resistance genes, and horizontal gene transfer is thus a key factor in the fast evolution and emergence of multidrug-resistant bacteria.

In hospital environments with the abundance of antibiotics the selective pressures are constantly present. With a variety of different bacterial strains and species with different levels of resistance, it is not hard to imagine how superbugs arise. These multidrug resistant strains, such as MRSA, are capable of serious, life-threatening infections that are difficult to manage due to limited treatment options. The impact of resistance will be clearly noticeable in a large increase in patient mortality (by around 50%, as shown by WHO), morbidity (length of hospital stay and complications), outbreaks of disease and raised costs to society. Young children, the elderly and people with compromised immune systems will be especially vulnerable as antibiotic treatment options decline. In Britain, about 5,000 people die each year from resistant disease already, and the treatment of conditions such as malaria, pneumonia, AIDS and open wounds will become increasingly more difficult.

Replacement treatments are more costly, more toxic, and need much longer duration of treatment, sometimes in intensive care units. For example at present, multi-drug resistant strains of tuberculosis are extremely difficult to manage, and require two years of treatment with toxic and expensive drugs. And even then, only slightly over 50% of patients survive. An otherwise easily treatable TB infection can turn into a multidrug-resistant disease if the patient skips doses or fails to complete antibiotics treatment, often because they start to feel better and mistakenly think the antibiotic is no longer necessary.

What makes antibiotic resistance so problematic is the fact that there is a finite number of approaches one can undertake when designing a drug that kills off bacteria, but does not have toxic side effects on the patient. Antibiotics are classified based on where they act in the cell, i.e. what their targets are. Did you know that the last time a truly new class of antibiotics was discovered was 27 years ago? Since then, we have only been able to improve already existing drugs, altering them a little in resonance with the drift of mutation-induced changes.

Antibiotic resistance has the potential to become one of the world’s biggest public health challenges, requiring a serious response from our scientists, our industries and the community at large.
– Professor Ian Chubb, Australian Chief Scientist

Adapted from Centers for Disease Control and Prevention website. http://www.cdc.gov/media/dpk/2013/dpk-untreatable.html

With the lack of novel therapies in the pipeline, the best we can do is to attempt to slow down the development of resistant strains by:

• Adhering to strict prescription guidelines in the clinic (prescribing antibiotics appropriately and only when needed)

• Improving diagnostic tests

• Educating medical students to ensure best practice

• Reducing the unnecessary use of antibiotics as much as possible (in livestock and viral infections)

• Making sure patients are taking the full course prescribed to them

• Using vaccines to reduce infection rates, or even eradicate diseases

• Practicing better hygiene (also for animals)

• Global efforts to track the emergence and spread of resistant strains

• Bringing scientists, industry and society together to combat the problem

• Thinking of novel ways to target bacteria, for example, engineer viruses that only infect bacteria and not the host (bacteriophages)

• Raising public awareness (exemplifying European Antibiotic Awareness Day to keep the public alert to the threat and their role in diminishing it)

The World Health Organization recently published a 257-page report on “Antimicrobial resistance: global report on surveillance 2014” in April this year, warning that multidrug resistant strains have emerged in all 114 countries studied. Last-line treatments for some bacterial infections are already in use now, so the question is, what will happen when those stop working? With the alarming rate of bacterial evolution, we are inevitably heading into the post-antibiotic era of vulnerability. WHO’s 67th World Health Assembly committee meeting is taking place in Geneva at the time of writing this article (May 19-24th 2014), and will result in voting on a resolution for global action to fight antimicrobial resistance.

References:
Excellent online learning resource by Kenneth Todar, PhD: http://textbookofbacteriology.net/resantimicrobial.html

Mulvey, M. R. & Simor, A. E. (2009): “Antimicrobial resistance in hospitals: How concerned should we be?” CMAJ, 180(4)

Speech by Dr Margaret Chan, Director-General of the World Health Organization: “Antimicrobial resistance in the European Union and the world” Presented at a conference on: “Combating antimicrobial resistance: time for action”, Copenhagen, Denmark , 14th of March 2012. Accessible online at: http://www.who.int/dg/speeches/2012/amr_20120314/en/

Collection of Nature Microbiology Reviews on the subject, great for further reading: http://www.nature.com/reviews/focus/antimicrobial/index.html

Simon Prasad and Philippa Smith (2013): “Meeting the Threat of Antibiotic Resistance: Building a New Frontline Defence”.

Office of the Chief Scientist, Occasional Paper Series, Issue 7, Australian Government. Online Access: http://www.chiefscientist.gov.au/wp-content/uploads/OPS7-antibioticsPRINT.pdf