Thursday, 2 October 2014

The rise of antibiotic resistant bacteria

Source: Flickr
Antibiotics were one of the greatest discoveries of all time, but ever since the advent of antibiotics, there has also been a rise of antibiotic resistant bacteria. These bacteria are partially or fully immune to the effects of the most common antibiotics like penicillin and erythromycin. What's even more startling is that antibiotic resistance to the less common 'last resort' styled antibiotics is also increasing, and at this rate we could be running out of drugs that are able to save people from life threatening infections.

How do antibiotics work?

Drugs work by binding to a receptor and either stimulating or inhibiting the receptor. This is what causes the drug to have an effect in the body. Antibiotics are no different in this regard and work through a similar mechanism.

The first antibiotic, penicillin, was able to kill bacteria by inhibiting the production of vital materials required to build cell walls. This is possible because penicillin binds to penicillin binding proteins. These proteins act to build the bacterial cell wall, but when penicillin binds to them instead of their natural substrate, the cell wall can't be completed. Without this vital component, the bacteria dies.

Humans however, don't have penicillin binding proteins and the penicillin doesn't have a natural target within the human body. This means that the antibiotic has selective toxicity towards bacteria but does not harm humans who take the medication. Antibiotics like this are bactericidal.

Bacteriostatic antibiotics, on the other hand, still inhibit vital bacterial function, but they don't kill the bacteria. These types of antibiotics stop the bacteria from growing and reproducing so that the body can kill them off more effectively. At higher dosages, many bacteriostatic antibiotics will have a bactericidal effect.

Antibiotic resistant tuberculosis
Mycobacterium tuberculosis - one of the bacteria developing resistance to conventional antibiotics
Source: Flickr

What is antibiotic resistance?

Antibiotic resistance is a problem because of the way antibiotics work. Because antibiotics need to inhibit the functions of bacteria, if a population of bacteria changes the way it performs that function, it will no longer be susceptible to the same antibiotic.

In the case of penicillin antibiotics, bacteria overcame penicillin through the production of an enzyme called beta lactamase. Penicillin, methicillin, and other antibiotics in the penicillin class, and to a lesser extent, in the cephalosporin class, are all able to bind to penicillin binding receptors because they are similar in shape and size to the natural substrate. The beta lactam ring within their structure is crucial to this. Bacteria beta lactamase attacks the beta lactam ring and breaks down these antibiotics before they can interfere with the cell wall. The bacteria is safe, and the drug is useless.

Other antibiotics work through different mechanisms. Sulfonamide binds to dihydrofolate reductase and acts to prevent the production of tetrahydrofolic acid, which the bacteria require for DNA synthesis. Antibiotic resistant bacteria circumvent this mechanism of action by using folic acid in their environment, rather than synthesising it themselves.

What causes antibiotic resistance?

The simplest answer to what causes antibiotic resistance is that the use of antibiotics causes antibiotic resistance. The more that a particular antibiotic is used, the more likely that populations of antibiotic resistant bacteria will be formed through artificial selection.

Source: Flickr

Bacteria are very diverse, because they multiply rapidly, undergo random mutations, and they can even share genes with other bacteria of the same species, or even bacteria of different species, through a process called horizontal transfer. All of these things contribute to a vast population of bacteria that vary slightly.

When treated with antibiotics, the bacteria that are naturally sensitive to the antibiotics are killed off. Bacteria that are resistant to the antibiotics, however, are not killed by the antibiotics, and it is these bacteria that live on and multiply. The more an antibiotic is used, the less of the naturally sensitive bacteria that is left. Before long, the resistant strains are more common than the previous antibiotic sensitive strain and infections can't be treated with that same antibiotic.

Worse still is that through processes like horizontal transfer, a resistant strain of bacteria can transfer its plasmid to another bacteria, effectively sharing genes that offer resistance to antibiotics. This dramatically speeds up the build of resistance because immune populations can share their immunity with sensitive populations.

There is no way to avoid antibiotic resistance other than to stop using antibiotics, and that would mostly be a moot point because the end result of resistance or avoidance is that people will die from common infections. Because we can't simply stop using antibiotics, but antibiotics foster resistance through the very mechanism by which they work, we need to devise other mechanisms to circumvent bacterial resistance.

Source: Flickr

Beating antibiotic resistance

There are a few different ways that antibiotic resistant bacteria can be made more susceptible to the same antibiotics they have become immune to. This is mostly a new area of treatment, and the mechanisms available to achieve this immunity reversal are limited so far, but it is still a promising area of health care. These range from clavulanic acid, which has widespread usage, to techniques involving pitting beneficial bacteria against pathogens, or turning off immunity genes in resistant bacteria.

Clavulanic acid

Clavulanic acid is one of the ways that antibiotic resistance can be countered in bacteria that are immune to the effects of beta lactam antibiotics like penicillin and methicillin. These bacteria produce the beta lactamase enzyme, which deactivates antibiotics in the penicillin class before they can kill the bacteria.

Clavulanic acid fights back against this defense mechanism by inhibiting beta lactamase. By binding to the bacterial enzyme and inhibiting it, the penicillin antibiotic is able to survive the enzyme and bind to the penicillin binding protein, inhibiting cell wall formation and killing the bacteria.

It is for this reason that many penicillin antibiotics are combined with clavulanic acid, to circumvent antibiotic resistance in bacteria and kill off infections. Amoxicillin and clavulanic acid is commonly used like this to treat tonsillitis and other infections under the Augmentin brand. As long as the combination is still effective, it is better to use this combo than to expose the bacteria to a different kind of antibiotic where there is currently no immunity or little immunity present in the wild population.

Probiotic therapy

Probiotic therapy is a fairly new way to treat infectious disease, and it's still in a development stage. The principle behind this form of treatment is that different species of bacteria will compete with each other. Most people have been introduced to this concept through fermented dairy products like yogurt.
Source: Flickr

Yogurt, as the epitome of probiotics, is a prime example of how this kind of treatment works. When antibiotics are given to a person for a longer length of treatment, the intestinal flora is often devastated. This is bad for several reasons. It is these beneficial bacteria that keep your digestive system running smoothly and help your body digest food, and their absence can lead to problems with bloating and indigestion.

Worse than that however, is that opportunistic pathogens like C. difficile are able to grow beyond control once the natural flora is disrupted. This bacteria is dangerous and can even be life threatening. Normally, lactobacillus and other species of beneficial bacteria prevent C. difficile from ever becoming a problem, but in conditions where the beneficial bacteria are diminished, C. difficile grows out of control.

This is exactly the same concept behind probiotic therapy. By introducing 'good' bacteria into the body, it may be possible to fight pathogenic bacteria without even using antibiotics. If scientists are able to engineer bacteria with particular genes that aid them in this fight, it may even be possible to design biological weapons that will wage war against infectious disease.

Bacterial gene therapy

One of the other techniques making significant headway to combat antibiotic resistant bacteria is a form of gene therapy, where bacteriophages are used to turn off antibiotic resistance genes in bacteria.
Source: Flickr

Bacteriophages are interesting in that they are viruses that use bacteria to replicate. These viruses are harmful to the bacteria because the inject their own DNA into the bacteria and force it to produce new copies of the virus. This is similar to how a regular virus would infect a human cell and use it to reproduce.

The benefit here is that bacteriophages possess a natural ability to insert DNA into bacteria. If bacteriophages can be modified to turn off the bacteria's resistance genes, that bacterium will no longer be immune to antibiotics. If the bacterium then shares these new genes through horizontal transfer, it will transfer this sensitivity to a new bacterium, and so on, so forth until an entire population is weakened.

This type of treatment would be slow to work and wouldn't hold much promise for treating infections in a host, but it could potentially become a more broad measure used to influence bacteria in the wild, decreasing the amount of bacteria that are resistant to antibiotics over time as the bacteria interact with each other and share genes.

The future of antibiotics

Although the rise of antibiotic resistant bacteria is certainly grim, the future isn't as bleak as you may believe from the news. Yes, there are now bacteria that are immune to last resort antibiotics like gentamycin and vancomycin, but there is also plenty of new research and potential ways to combat this resistance. The future of antibiotics is unclear as of yet.

Furthermore, new antibiotics are still being discovered, and there are new ways to modify existing compounds to circumvent resistance. As long as dangerous bacteria exist and cause illnesses in humans, new ways to fight back against this threat will always be on the horizon.

More information

  • Nanomedicine - the future of health
    Nanomedicine is an exciting new area of medicine, involving the use of nanotechnology. This form of medicine is already being used to help treat cancer and other deadly diseases. It may even have the capacity to cure the deadliest illnesses of the century.

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