- Merel Sijbranda
How diversity can be powerful: Mycobacterium tuberculosis and antibiotic resistance
The other day I visited my grandparents, and I told them about this mini-series I’m writing about tuberculosis (TB). We got into a conversation about the presence of TB in their youth. As they described the TB patients lying in hospital beds in the open air of a sanatorium (a specialised hospital to treat TB patients), I was reminded of the old idea that outdoor air was restorative for TB. With the lack of further knowledge on TB and TB treatment at that time, tuberculosis was often ‘treated’ by keeping patients in the fresh air, and this worked pretty well actually. But although it was the best medicine back then, it definitely wasn’t curative.
Fortunately, we’re well past that era. We know more about tuberculosis and the bacteria causing the disease nowadays. With the discovery that tuberculosis was caused by bacteria, came opportunities. Antibiotics - used to treat bacterial infections (as opposed to viral or fungal infections) - were introduced a few decades after the discovery of Mycobacterium tuberculosis (Mtb) and were directly applied to treat TB. This led to a major breakthrough in tuberculosis treatment, and antibiotics have been seen as the ‘magic bullets’ to treat TB ever since.
At this moment, the standard treatment for TB generally comprises a 6-month stretch of the use of various antibiotics. The combination of the different antibiotics is composed in a way that it unarms the bug on various fronts. If you’ve read the first blog of this mini-series, you might recall the undeniable importance of the cell wall for Mtb – Mtb’s ‘skin’, that thick, waxy layer on the outside of Mtb. With the cell wall being key for Mtb’s survival, it comes as no surprise that this particular feature of Mtb is often the target for antibiotics.
Isoniazid, one of the most powerful antibiotics used in TB treatment, tackles specifically this power feature of Mtb. It blocks the formation of Mtb’s thick, waxy ‘skin’ – and remember, that ‘skin’ is necessary for Mtb to stay so well in shape and isolated from our immune systems! With this layer unable to form properly, the Mtb is left uncovered and skinned (ew!). Without its skin, it can do nothing more than die eventually. Which is exactly want we want to achieve when giving this drug. Perfect!
However, with the introduction of - what was thought to be – our saviour from TB, also came trouble… A clear rise in multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of Mtb, which are resistant to at least two or four of the most effective drugs respectively, has been observed over the past years. These Mtb strains are becoming a major concern in the treatment of TB. Of course, Mtb managed to circumvent the directed attacks again - but this time not counter-attacks by the body but by drugs.
Let’s take a closer look at the development of antibiotic resistance of Mtb. And in fact, it has everything to do with a common topic at this moment in time: diversity.
You might think of the population of Mycobacterium tuberculosis bacteria as being one homogenous group of annoying little bugs. Like a little army of ants, all seemingly alike. Indeed, I also presented it like this in the other blog posts (here, and here) for clarity – my bad. But in fact, there dwells a huge variety in the Mtb population within and across individual human patients. A beautiful collection of diversity, actually – just as we have in our human population. Our human population has an amazing variety of different appearances and behaviours. And this is nothing different from the population of Mtb bacteria in the body during infection. Turns out, being greatly diverse is Mycobacterium tuberculosis’ major superpower when it comes to resistance to external attacks, from our own body – our immune system – and from prescribed drugs.
To explain how this diversity drives resistance, we go back to our beautiful human population.
Look at the humans around you, on the streets, in the library. All our appearances differ. Only to name one example: there are people with more light-toned skin, and people with a more dark-toned skin. There are, however, some environments in which specific skin tones may be more advantageous – biologically speaking - than others. For example, people with more dark-toned skin are less prone to get a sunburn after a long day in the burning sun, compared to people with light-toned skin (like me, a typical Dutchie who is very likely to get sunburned…). Just like humans, each individual Mtb also has a slightly different ‘skin’. And what represented the ‘skin’ of Mtb, again? Right, the cell wall. So, like every human’s skin tone, every Mtb’s cell wall differs slightly. The building blocks of the cell wall just slightly differ from one Mtb to another, for example. And it just happens that some ‘skin tones’ of Mtb will be more susceptible to a given antibiotic, while other skins will be more resistant.
This comes with some – not all so fun - consequences. When introducing an antibiotic drug to Mtb, the bacteria with more susceptible skin will be killed by the antibiotic – great! However, some of the Mtb could have a more ‘resistant’ skin, and stay alive. The father of evolution, Darwin, would say: ‘survival of the fittest’. The fittest – in this case, the ones with a more resistant type of skin - survive. Those bacteria can enjoy the ‘joie de vivre’, grow and reproduce. Eventually, we end up with a population composed of more Mtb bacteria with resistant skins, and fewer with susceptible skins. And in that case, the treatment will not be effective…
And that’s not the only trick up Mtb’s sleeve. Mtb is versatile, just like humans. Besides differences in people’s appearances, humans also differ in behaviour. There are people that like to stay in, whereas others prefer a walk in the fresh forest air. People with an eternal overloaded agenda - the busy bees - and people that like to take it more slowly. The different Mtb bacteria present in the body at the time of infection are just like that. They vary in behavioural traits as well.
By behaving differently, the ones that are not accidentally blessed with a great skin can still take their shot at surviving the antibiotics. This is just another example of Mtb being smart - and we’ve already seen how smart Mtb can be in the first and second articles in this mini-series.
So, how do Mtb bacteria differ in behaviour? Actually, perhaps without noticing, you’ve already come across two examples of behavioural changes in the previous blog post. Do you remember the big fortress containing sleepy Mtb bacteria?
Well, smart Mtb simply like to stay in. And specifically, inside the filthy, desolated, well-guarded fortress that they build inside the lungs of infected humans - the caseous granuloma. In this fortress, they are way harder for the antibiotics to reach. The drugs have to go inside the secluded fortress to act on the Mtb. And we’ve just seen in the last blog post that immune cells try to do their ultimate best to build a big, firm wall to lock up the bacteria. So, it seems that the solution of the body to achieve a truce between the body and Mtb – the building of a granuloma fortress - is also complicating the total killing of the bacteria by antibiotics. Darn it!
Fortunately, some drugs do have the capability to sneak through the backdoors of the fortress. However, it could be that they are still not able to kill off all of the Mtb inside the fortress. Why? Because of Mtb’s behaviour inside the fortress: sleepy, bland and non-growing. When you’re like this inside a big fortress, you can imagine that people won’t notice your presence that much. In contrast, you can’t miss the busy bee-Mtb. With the sleepy, energy-saving mode turned on in those Mtb bacteria, a lot of general processes - which are up and running in more active Mtb bacteria - are switched off. Simply, to save energy. The problem is that some of our antibiotics work against proteins that are only switched on when these general processes are switched on, which means they kill only the busy bee-types of Mtb bacteria. With those processes running on the back burner, the antibiotics do not work as well for sleepy ones…
And this is particularly the case for isoniazid. Isoniazid blocks the creation of new cell walls of Mtb bacteria. The only thing is... making new cell walls mostly happens when the Mtb are active and reproducing. Unlike the busy bees, the sleepy bacteria are in energy-saving mode, so they don’t actively need to make new wax. This means that only the active busy bee-type Mtb bacteria are tortured by antibiotics like isoniazid...
But we have a solution here. This is exactly the reason why we always treat patients with a good mixture of different antibiotics that all target different processes. Combining forces is always a good idea!
Nonetheless, because of this massive variety in Mtb bacteria – in appearance as well as in behaviour – it could still occur that a few bacteria are totally fine and compatible with the total combination of different antibiotics. And those are exactly the ones that can continue to grow, reproduce, and take over. Leaving us with a population of highly resistant bacteria…
There is also one major societal aspect that we’re missing in the antibiotic resistance story. And that is that MDR and XDR strains often arise from misuse and mismanagement of TB antibiotics. The reason TB treatment takes so long is because it takes time and effort to kill the whole population of diverse Mtb bacteria. Without finishing the full months-long treatment period, more Mtb are likely to persist. Low-income countries often lack access to the right amount of drugs, as well as guidance and support to facilitate regular drug intake. Patients facing a months-long treatment with at least four different drugs are likely to drop out after some time of noticed improvement. You might have experienced something similar yourself – if your doctor prescribes you 10 days of antibiotics but you feel better after 5, you might be tempted to stop taking the drugs. You can imagine this could be even more the case when treatment takes up to 6 months (or more) and when you are not aware of the dangers. However, not finishing treatment is exactly what gives rise to the development of MDR and XDR Mtb strains.
To end, with the introduction of new antibiotics, new antibiotic resistant strains will always pop up. Although we are getting better at seeing the pitfalls of certain antibiotics and know how to manage those, this is not the sole solution. As stated in Cell (one of the most respected biological journals): “To truly stem the tide of tuberculosis, we need new and effective vaccines.” We have to look for a new ‘magic bullet’.
Just a few weeks ago, the WHO announced plans to establish a new TB Vaccine Accelerator Council. With the century-old BCG vaccine – the current TB vaccine – on its decline, it is time for something new. Vaccines are different from antibiotics in that they help our immune systems to gain some artillery, so they can fight off the bacteria themselves. And in addition, with a vaccine you prevent disease on a population level, rather than problem-solving on an individual level with antibiotics - to which Mtb can develop resistance. While we don’t have a new vaccine yet, we are on our way. But until then, Mtb is still the big winner in this constant battle. And diversity is its key to success. Maybe we can learn from Mycobacterium tuberculosis in that perspective.
If you’ve been with me for the whole mini-series, you might have noticed how everything I told you about Mtb is interconnected. This is a perfect example of biology, in fact. Everything is complex. But that’s also why it is so cool. I hope I’ve sparked some enthusiasm for this fascinating microbe and you enjoyed reading the posts!
Thanks a lot for reading (a part of) the mini-series, it has been a great joy!
Other resources used to write this blog:
Types and functions of heterogeneity in mycobacteria | Nature Reviews Microbiology
Frontiers | The evolving biology of Mycobacterium tuberculosis drug resistance (frontiersin.org)
Anti-tuberculosis treatment strategies and drug development: challenges and priorities | Nature Reviews Microbiology
Tuberculosis: a problem with persistence | Nature Reviews Microbiology