Mutation makes TB resistant to common antibiotics

Scientists have found that tuberculosis strains (TBs) with an allegedly lethal mutation can actually survive — and that the mutation makes the bacteria resistant to a significant antibiotic.

Uppsala University scientists in Sweden have discovered that tuberculosis can survive a mutation that theoretically should kill it.

In addition, the team found that this mutation had made antibiotic rifampicin resistant to the affected TB strains. Rifampicin is the most effective first-line medicine for the treatment of TB infections according to the World Health Organization (WHO).

The researchers described their discovery in the journal Proceedings of the United States of America’s National Academy of Sciences.

What is TB?

TB is a bacterial infection which is preventable and treatable. It typically affects the lungs of a person but other parts of the body may have signs and symptoms.

As the Centers for Disease Control and Prevention (CDC) explains, tuberculosis is an airborne infection— it spreads when someone in their lungs or throat coughs has an active TB infection, talks or sings.

In 2018, 1.5 million people died from TB worldwide, and there were 9,025 cases of TB in the United States.

Treating tuberculosis typically requires a person to take 4 antibiotics 6–9 months. Since TB develops resistance to many antibiotics, it’s important to predict which drugs are likely to be effective.

Scientists and doctors can now use DNA sequencing to determine which antibiotics to treat the form of TB behind each infection.

It involves taking a sample of TB bacteria from a person with an active infection, evaluating the DNA profile of the bacteria, and identifying the strains of the present bacteria and what antibiotics they have probably developed resistance to.

A supposedly lethal mutation

The antibiotic rifampicin targets the essential RpoB protein of TB, without which TB can not survive.

The team behind the present study noticed that a lot of clinical TB bacteria had a gene mutation that produced the protein RpoB.

The researchers presumed this mutation would stop the protein from being produced, thus preventing the survival of these TB strains.

Despite the mutation, and despite antibiotic treatment, the affected bacteria were able to continue to develop.

To explore the mechanisms behind the survival of the bacteria, the scientists isolated a similar mutant gene in the bacteria Escherichia coli, a type that is easier to experiment with and less likely to cause harm than TB.

By studying the mutation in the RpoB protein, the scientists have been able to understand how the bacteria could develop further.

‘Slippery’ DNA

The mutation was causing a rare type of “slippery” DNA sequence in RpoB-producing genes, according to the researchers.

They found that when a ribosome— a type of biological machine that produces proteins in all cells— reads this part of the DNA sequence it slipped, making many mistakes.

In the end this suppressed the mutation effect in the RpoB-producing genes, allowing the affected strains to survive.

The RpoB protein also mutated as a result of this suppression, making the TB resistant to antibiotic rifampicin.

Not only do these results clarify how TB survived an apparently lethal mutation— they point to potential pitfalls in existing approaches to DNA sequencing for TB and other infectious pathogens.

DNA sequencing is a modern and efficient means of improving our knowledge of the characteristics of an infectious agent— including, in the case of TB, its antibiotic resistance.

However, the present study shows that the analysis of DNA sequences has room for improvement.

The researchers observe that “the high frequency of such mutations in genome sequences strongly motivates the need to develop improved predictive genotype to phenotype methods,”

which is important in ensuring a person’s infection is diagnosed and treated quickly and, above all, correctly. If scientists assume that the bacteria will be killed by genetic mutations in TB, and this does not happen, it could prolong diagnostic and treatment processes.

A delay in diagnosis in a person with a disease such as TB raises both the probability of the person contracting the infection and the possibility that the infection may grow untreated and become life threatening.


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