19 7 / 2014
Anonymous said: I miss this blog, are you going to update it soon?
Yes, I had to take a hiatus for personal reasons but this blog will be back with new content which I am currently in the process of planning. Keep your eyes open!
12 12 / 2013
Antibiotic resistance spreads in a number of ways. For simplicity, we will look at three main categories. The first of which is molecular spread
Many people are familiar with the idea of DNA in a cell. In our cells, DNA is packaged neatly into chromosomes and is safely locked inside a compartment known as the nucleus. Bacteria have no nucleus and they have one large circular bit of DNA (the chromosome) and sometimes some smaller circular bits of DNA (plasmids). Bacteria are able to move DNA around and pass it between each other and this is one of the ways resistance can spread. There are actually several ways this can happen. So let’s imagine our favourite bacterium has some DNA, a gene, that makes it resistant to penicillin…
1) Viruses, known as bacteriophage, can get into the bacterial cell. Once the viruses are in, they can make lots more copies of viruses. The new viruses can burst out of the bacterium and then enter neighbouring bacteria to repeat the cycle. Imagine if the virus could take the penicillin resistance gene with it and transfer it to a neighbouring bacterium which didn’t have that resistance gene previously. If the virus stays dormant in the new bacterium, the bacterium can use this new resistance gene to its advantage! This is called transduction.
2) As described earlier, bacteria have plasmids. A plasmid could contain our penicillin resistance gene. Bacteria are able to share these plasmids with neighbouring bacteria, who may not have had this resistance gene previously, by getting really close and personal with each other. This is called conjugation.
3) Bacteria are sometimes able to take up DNA from their environment. So, if a bacterium containing a resistance gene dies and releases its DNA into the open environment, another bacterium can take up this DNA and acquire the resistance gene. This process is known as transformation. Interestingly, some bacteria actually ”commit suicide”, so to speak, in order to release their resistance genes into the environment for the greater good of the bacterial populations!
25 9 / 2013
To understand how bacteria become resistant to antibiotics on a molecular level, the way antibiotics work must first be explained. In a later post I will explain how resistance spreads but for now we will focus on the molecular mechanisms involved in resistance development.
Antibiotics mainly target and disrupt 3 fundamental processes in bacteria:
1) Cell wall biosynthesis
2) Protein synthesis
3) DNA replication and repair
An important thing to remember is that antibiotics MUST target fundamental processes that are different in bacteria than in our own cells. We wouldn’t want antibiotics to work on our cells because then they would be toxic! Below is an example of the resistance mechanisms that developed to prevent the action of penicillin.
Targetting Cell Walls - The Penicillin Example
How it works: Penicillin is an example of the class of antibiotic that targets bacterial cell walls. It doesn’t affect our own cells because eukaryotic cells don’t have cell walls. Bacterial cell walls are made up of glycan strands which are linked up by peptidoglycan units known as NAG and NAM. A bacterial enzyme, transpeptidase, joins up all the NAM molecules as you can see below. This makes the bacterial wall strong and protective. However, bacteria need to grow so sometimes they unpick the links between NAM molecules so that they can lay down more building blocks and expand. Following expansion, the NAM molecules are joined back up to provide strength once more.
Penicillin binds and modifies the transpeptidase enzyme so that NAM molecules do not get joined up quick enough. However penicillin does not prevent the cell from unpicking NAM links during expansion. So the overall result is that the cell unpicks the NAM links but isn’t able to then link them back together. This causes the cell to burst and die.
How resistance developed: In the case of penicillin, resistance develops quite simply. The gene that encodes the transpeptidase protein is mutated. The transpeptidase enzyme is altered in such a way that penicillin can’t bind and modify it and cell wall building goes on as usual.
Many people have heard of MRSA or methicillin resistant Staphylococcus aureus. It is often described as a superbug, is the leading cause of hospital acquired infections and is responsible for up to 40,000 deaths a year. It is resistant to many antibiotics including penicillin. MRSA has developed resistance to penicillin by creating a completely new transpeptidase enzyme instead of just mutating the old one. Penicillin does not work on this new transpeptidase.
What types of resistance are there?
Aside from preventing the antibiotic from acting on enzymes important to the bacterium there are several other ways that bacteria can become resistant. They can:
- Pump out the antibiotic
- Destroy the antibiotic
- Become impermeable to the antibiotic
Does resistance develop to all antibiotics?
Molecular resistance mechanisms will develop, it is more a question of when and how. The development of resistance mechanisms is a natural part of evolution in which bacteria simply become better at surviving. Resistance develops in the following way:
- You have a pool of bacteria in an infection which are being attacked by an antibiotic
- Mutations occur in bacteria when they are dividing
- Statistically, there is a chance that at least 1 bacterium will mutate in such a way that the antibiotic won’t affect it, like we discussed with penicillin.
- That 1 bacterium now has an increased chance of survival compared to the other bacteria that haven’t mutated, it has become resistant
- That 1 bacterium will divide and produce more bacteria that also have this increased chance of survival
- Eventually, the infection pool will be made up mostly of the bacteria with this resistance
- The pool is now resistant to the antibiotic
In any infection, there are large numbers of bacteria. To make matters worse, bacteria divide and new bacteria are generated very rapidly. If you imagine that there is a mutation rate of 1 in 107 and there are 1010 bacteria in a particular infection pool it is easy to see how the above scenario would occur. So, statistically, resistance will develop at some point in some infection. The problem doesn’t end here though. If this was the only trick up the bacterial sleeve, then resistance could be contained more easily. Bacteria are able to do what is known as horizontal gene transfer. They can pass their genes to other bacteria in their pool, not just to their daughters. So if you have a resistant bacterium lying around on a remote control in a hospital, it can pass its resistance on to other bacteria in the general environment.
To put everything into context, it’s useful to look at vancomycin as an example of the inevitable resistance that arises. Vancomycin, discovered in the 50s, is an antibiotic of ‘last-resort’ treatment and is sometimes used to treat serious MRSA cases. It took approximately 30 years for resistance to vancomycin to happen but it did. The resistance that developed is highly complex which is why it has taken so long but this should serve as an example that even really powerful antibiotics will be evolved around eventually. This is why the scientific community must endeavor to discover or create new classes of antibiotic. However, this is not enough. As we approach a public health crisis, we must think of new ways to treat bacterial infections and we must amend policy to slow down the approach of the post-antibiotic era.
17 9 / 2013
Most people are familiar with the story surrounding the accidental discovery of penicillin by Alexander Fleming in 1928. Fleming left a culture plate of Staphylococcus lying around in the lab for two weeks while he was on vacation, only to return and find the plate had become contaminated with Penicillium fungus/mold. The Staphylococcus bacteria seemed unable to grow near the mold and he concluded that Penicillium prevented the growth of these bacteria.
Few are familiar with Howard Florey and Ernst Chain, two of several scientists who would take this observation and change the course of public health. Penicillin first needed to be purified and concentrated efficiently and this process was as painstaking as it was time consuming. Subsequently, penicillin was tested in mice and it was found that all mice that were given penicillin lived whilst untreated mice died. In 1941, penicillin was administered to patients for the first time and it was noted that if the penicillin supply ran out before the completion of treatment the patient would relapse and die. It was clear by this point that pharmaceutical firms were needed to produce penicillin on the scale required.
By this point, World War II was raging on and one of the most important decisions in the history of science was about to be made. Chain wanted to patent penicillin but Florey believed this would have adverse consequences in the war climate of the time. Florey was committed to the idea that this discovery would and should benefit all mankind. Penicillin soon shot to fame as the “magic bullet” for infectious disease and the scientific community entered the golden era of antibiotic discovery (1945-1960) during which numerous new classes of antibiotics were discovered.
Fast forward about 60 years and the picture is somewhat different. Gone are the adverts proclaiming antibiotics cure all and we are instead faced with the prospect of entering the post-antibiotic era or, as many sensationalists like to call it, “pharmageddon”. Discovery of new classes of antibiotics is rare, as can be seen in the timeline above. Equally worrying is the spread of antibiotic resistance which is dismantling the arsenal of protection we have built up over the last decades. These are complex issues which pose a real threat to public health globally. We will look at how bacteria develop resistance to antibiotics, what the implications of this are, proposals to mitigate the issues and alternative solutions for treatment in the future.
(Timeline Source: Gerard Wright, Nature 2007)
16 9 / 2013
Anonymous said: If radiation causes cancer then why do doctors treat cancer with radiotherapy?
Great question! I hope this answer is detailed enough for you (there’s quite a bit of background information to get through first).
So first of all, I should clarify the term ‘radiation’. Radiation can be ionizing (high energy and harmful) or non-ionizing (low energy and not generally harmful). X-rays and gamma rays are types of ionizing radiation and can be harmful whereas visible light is an example of non-ionizing radiation which isn’t harmful. UV rays can be ionizing and non-ionizing, however most ionizing UV rays get filtered out by our atmosphere before they reach us. Nevertheless, UV rays can cause damage through other means.
Ionizing radiation is so high in energy that it causes electrons to be ejected off atoms. So now you’ve got a negatively charged electron floating around as well as a positively charged atom. As a general rule of thumb, charged things like to react with other things and this is exactly what happens. As a result, you get the production of free radicals. Free radicals are things like hydrogen peroxide and they are super reactive! They can react with and damage the DNA backbone. You definitely do not want to damage your DNA because that contains all the information for how a cell should work and damaged DNA can lead to tumour formation if it is not repaired.
(Random cool fact: Mammalian cells can experience up to 200,000 hits which cause damage per day! Your cells successfully deal with damage all the time!)
In general, ionizing radiation causes double-stranded breaks, single-stranded breaks and cross-linking within a DNA molecule. You can see what this damage looks like in the image below. Double and single stranded breaks occur when the DNA backbone is disrupted whilst cross-linking is when the bases within the DNA form covalent bonds with each other (as indicated by the red line, here only what is known as intrastrand cross-linking is shown for simplicity).
In “normal” cells, there are a number of different repair mechanisms to fix all these types of DNA damage (though sometimes these can fail and lead to cancer). In cancer cells, repair mechanisms are often impaired. The purpose of radiotherapy is to try to target only cancer cells which do not have the capability of repairing the damage, thereby killing them or preventing them from growing further. This is why cancers which have heightened repair mechanisms such as gliomas are often resistant to radiation treatment. Chemotherapy works similarly, the aim is again to damage the DNA of cancer cells.
19 8 / 2013
Anonymous said: My biology teacher told us about antibiotic resistance today. Can you explain how this affects countries and what is going on?
Antibiotics, the way they are used, problems in their availability to developing nations and resistance are actually topics I’m really interested in. I don’t think a brief answer will do this topic justice but I’ve been planning an in depth series of posts on this for a while so keep an eye out and I promise you’ll hear something soon!