Debunking myths on genetics and DNA

Friday, January 6, 2012

The curse of drug-resistant TB strains

Tuberculosis (TB) is a disease caused by a number of strains of mycobacteria. It affects mostly the lungs with chronic, bloody cough and fever. It can remain asymptomatic as a latent infection, though about 10% of these latent infections eventually progress to active disease.

The two most common drugs used to treat TB are isoniazid and rifampicin, but unfortunately new mycobacteria strains (called MDR strains, which stands for multi-drug resistant) have emerged that are resistant to both these powerful drugs. In other words, the pathogens have developed certain mutations that make them "immune" to the drugs. As with HIV, common thought is that these drug-resistant strains emerge during the course of the treatment in single individuals as a result of the selection pressure induced by the drugs. This is also reinforced by the fact that typically drug-resistant mutations confer a cost of fitness: though able to escape the drugs, the mutated strains tend to reproduce less quickly and/or are not able to be transmitted.

Unfortunately, that's not always true. A study published by Nature Genetics in December [1] showed that MDR TB strains do not show a fitness cost and that the most common drug-resistant mutation is present in the population with a wide variety of compensatory mutations. These are additional mutations that compensate for the loss of fitness by working in antagonistic epistasis to lessen the structural and functional instability of the affected proteins.

Comas et al. compared
"the genome sequences of ten paired clinical rifampicin-resistant isolates to the genomes of the corresponding rifampicin-susceptible isolates recovered from the same infected individual at an earlier time point. We identified all nonsynonymous and intergenic mutations found only in the rifampicin-resistant genomes. In addition, we experimentally evolved six laboratory-derived rifampicin-resistant mutants from rifampicin-susceptible ancestors during 45 weeks of serial subculture in the absence of rifampicin."
They showed that
"The high frequency of compensatory mutations in strains from Abkhazia/Georgia, Uzbekistan and Kazakhstan is consistent with the success of MDR strains in these regions, where up to 50% of individuals with TB are estimated to carry MDR strains compared to a global average of only 3%."
These findings are particularly relevant for TB treatment policies: isoniazid and rifampicin have been used not only to treat infected patients, but also as a preventive measure for people visiting countries with high TB prevalence (as for example peace corps). Furthermore, people are treated as soon as they become TB positive, but for the most part these infection are latent and all genetic information we have on TB is from active infections. There's no way to know if these drugs are effective until the infection becomes active. If these MTR strains are not only fit but also transmissible, the persistent use of these drugs will have the net effect of allowing breeding and spreading drug-resistant strains, resulting in a rise of non-treatable infections.
"In conclusion, our results suggest that the acquisition over time of particular mutations in rpoA and rpoC in rifampicin-resistant M. tuberculosis strains leads to the emergence of MDR strains with high fitness. Furthermore, our data show that these mutations occur at high frequencies in clinical settings, particularly in hotspot regions of MDR TB9. Additional studies are needed to determine whether MDR strains of M. tuberculosis with mutations in rpoA or rpoC have increased transmission rates and how these mutations contribute to the success of these strains. Use of targeted genotyping of these mutations will enable TB control programs to focus on the most transmissible MDR strains. Our findings also suggest that mathematical models that aim at predicting the future of the global MDR TB epidemic should take into account the effects of compensatory mutations as well as the time necessary for such mutations to emerge."

[1] Comas, I., Borrell, S., Roetzer, A., Rose, G., Malla, B., Kato-Maeda, M., Galagan, J., Niemann, S., & Gagneux, S. (2011). Whole-genome sequencing of rifampicin-resistant Mycobacterium tuberculosis strains identifies compensatory mutations in RNA polymerase genes Nature Genetics, 44 (1), 106-110 DOI: 10.1038/ng.1038

Photo: making progress with my macro lens! Canon 40D, focal length 100mm, shutter speed 1/100, F-stop 14, ISO speed 100.

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  1. Interesting as always! I wonder, do most viral/bacterial "diseases" share this ability to evolve resistant mutations or are there categories (HIV, TB, MRSA?) that are especially good at it?

  2. @Steve: All bacteria are capable of mutating, but there are some bacteria that are more willing to share their DNA than others, allowing the resistance to spread faster. Staph aureus, paradoxically, is not wonderfully good at sharing DNA around, but it's found one spectacular party trick and it utilising it well.

    Interestingly enough the more stress you put bacteria under, the *more* they mutate in a sort of "evolve quick or die" response. Bacteria that are almost wiped out by antibiotics are therefore far more likely to evolve resistance than those that just exist happily in the normal population.

  3. Thanks, Lab Rat, that's really interesting. The same happens with viruses: the ones that mutate faster (HIV, influenza) will evolve more rapidly, but there's a threshold in how big a mutation rate can be: if you can tweak the mutation rate to be over a certain threshold, at that point the virus mutates so rapidly that most mutations start being deleterious and the virus will eventually go extinct.

  4. Thanks for the answers, both of you. Very interesting.

  5. An addendum from my dad: the ability to evolve such mutations probably pertains to numerous organisms, so long as they are aploid. That's because mutations in diploid organisms – whether advantageous or not – may or may not be expressed phenotypically. If they aren't expressed phenotypically they may or may not persist.


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