Antibiotic resistant bacteria pose a high risk to human health and have become increasingly prevalent in recent years as a result of elevated and improper use of antibiotics. These antibiotic resistant bacteria, some of which may sound familiar (MRSA, or Methicillin-resistant Staphylococcus aureus, is a particularly recurrent concern), have adapted to evade the most effective treatments for bacterial infections. In 2019, a total of 1.27 million deaths worldwide were directly attributed to infections from antibiotic resistant bacteria. This problem is worsening every year, making antibiotic resistance one of the greatest threats to public health. What drives this crisis, and how can we address it?

What are antibiotics?

In almost all places on Earth, bacteria exist in dense populations anywhere from in soil, hot geysers, and even inside living organisms – including humans, though the majority of bacteria are not harmful to us. Bacteria frequently compete with one another for access to the nutrient resources available in nature. One important tool in this competition is the ability for bacteria to produce and secrete chemicals which can kill other bacterial competitors on contact, which we refer to as antibiotics. Biochemists have learned how to isolate these chemicals, identify them, and recreate them in laboratories for medicinal purposes; however, drug development is expensive and time consuming which stalls progress. Although finding antibiotics from wild bacteria is a well understood process, the risk of the harmful bacteria quickly developing resistance to the new antibiotic serves as a deterrent for undertaking novel antibiotic discovery. Research through universities and organizations like the Small World Initiative move the field in a positive direction, but results can hardly come quickly enough.

How does antibiotic resistance occur?

Bacteria develop resistance to antibiotics in multiple ways, some of which are dependent on previous exposure to an antibiotic while others will develop regardless of exposure. The main mechanisms for resistance include increasing natural defenses to prevent the drug from entering the bacterial cell, altering the antibiotic drugs once they enter the cell, and fully expelling the antibiotic from the bacterium cell through structures called efflux pumps (Figure 1). Some of these traits are acquired as genetic mutations. For example, a mutation that increases the strength of a bacterium’s outer membrane makes it harder for antibiotics to enter the bacterium in the first place. These mutations can be passed on to other bacteria through a process called horizontal gene transfer. Imagine if every time you shook hands with someone, you would both permanently swap some of your DNA – you would be constantly and rapidly changing! Horizontal gene transfer makes it possible for bacteria to exchange genetic information, which makes them mutate and adapt very quickly. Traits that make bacteria resistant to antibiotics can spread swiftly through populations, which further complicates the fight against antibiotic resistance. 

Depicts a bacterial cell and the targets of antibiotics. Efflux pumps appear as ports connecting the inside of the cell to the outside. Enzymes are depicted as colorful ribbons, which can be modified. DNA and protein complexes are also depicted and can be modified by antibiotics.
Figure 1: Mechanisms of Antibiotic Resistance. Efflux pumps enable many antibiotics to be fully expelled from the bacterium. Key components in antibiotics can be turned off inside of the bacterium. Important DNA and protein targets can be altered, rendering a previous treatment ineffective. Certain antibiotics can also be blocked before entering the bacterium.

 

Figure 1: Mechanisms of Antibiotic Resistance. Efflux pumps enable many antibiotics to be fully expelled from the bacterium. Key components in antibiotics can be turned off inside of the bacterium. Important DNA and protein targets can be altered, rendering a previous treatment ineffective. Certain antibiotics can also be blocked before entering the bacterium.

How can we fight resistant infections?

When a person develops a bacterial infection that is or becomes resistant to antibiotic treatments, there are a few options. First, the bacteria can be cultured and identified, which may guide further treatments. Antibiotics do not work on all bacteria, but often demonstrate ‘specificity’ in which they can only kill certain species. Second, some antibiotics are stronger, but also have intensely negative effects on the body and therefore are only used for especially dangerous infections. These medications are also kept in reserve to try to reduce the number of bacteria that have been exposed to them, therefore decreasing the resistant population size. By only treating infections that were already resistant to other antibiotics, these treatments can be trusted to wipe out the remaining infection. However, many bacterial species are slowly developing immunity to these treatments as well. To combat this issue, one of our most promising options is to fight fire with fire – or rather, an infection with an infection. 

Like us, bacteria can be infected by viruses, though viruses that affect bacteria are known as bacteriophages. The bacteriophage can pierce through the bacterial cell membrane and inject their own genetic material, which then hijacks the bacterial cell replication machinery to create new bacteriophages instead of new bacteria (Figure 2). The characteristics of bacteria that are most protected from bacteriophages often differ substantially from the characteristics that are best for resisting antibiotics. Some phages specifically target bacterial efflux pumps, which act as a door through which their DNA can enter the bacteria, increasing the odds of survival for bacteria that do not have efflux pumps. The bacteria that lack efflux pumps now have higher odds of surviving the phage therapy treatment, and these genes become favorable for other bacteria. Conveniently, this strategy also makes the bacteria vulnerable to antibiotics that were previously being flushed out of the efflux pumps in prior generations. By treating antibiotic resistant infections with a cocktail of both bacteriophages and antibiotics, this two-pronged attack introduces a new way of conquering antibiotic resistant diseases.

On the left is a labeled drawing of a phage which shows an icosahedral shaped geometric top which contains a strand of DNA and is labeled the "head" of the phage. Beneath the head is the "tail" which is a long connecting rod and then a base with multiple spidery-like legs labeled "fibers". Coming out the bottom of the base is a "spike" where DNA is ejected out of the phage. On the right is a drawing of a page poking its spike through a bacterial cell wall and injecting DNA. The DNA is then used to make more bacteriophage components and new phage are shown exiting the cell.
Figure 2: Diagram of Bacteriophage. Left: The labeled components of the bacteriophage, demonstrating the location of the DNA in the head, the spikes that can pierce the bacterium cell membrane, and where the DNA can be released from the bacteriophage. Right: Shows the bacteriophage injecting DNA into a bacterium where the DNA is then processed and new bacteriophages are produced.

That’s not to say that bacteriophage cocktail therapies are a simple solution. Phages often have high specificity, meaning that they will only target certain bacteria. Unlike broad-spectrum antibiotics, which have been used to treat a wide variety of bacterial infections, combinations of phages need to be tested and custom-selected on a per-infection basis to create a treatment. Large phage resources like SEA-PHAGES have been used to screen thousands of bacteriophages to find the best matches for a disease. Although some successful treatments have been developed from this method, it is also still slow and expensive – not what most people want to hear when describing treatments for a potentially fatal illness. 

The dawning era of personalized medicine offers the potential for exciting new treatments, but the bottleneck of time and resources slows its approach. To best fight the antibiotic resistance crisis, there are a few things you can do. If you are prescribed antibiotics, be sure to take the complete course as prescribed. Regardless of when your symptoms go away, the bacteria causing an infection may still be alive, and those bacteria that survived the longest are likely to have acquired new resistance. Additionally, try to avoid overusing antibiotics. Many illnesses are the result of viruses, not bacteria, so taking antibiotics will not reduce your symptoms or shorten the duration of your illness. However, benign bacteria that were not causing your infection will still have been exposed to the antibiotics and their genes can later be passed to disease-causing bacteria. By changing the culture surrounding antibiotic use, we can preserve the utility of these medications and buy researchers the time they need to develop new life-saving alternatives.

 

Peer Editors: Maggie DeMolina & Kaeli Welsh

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