Researchers find a way to reverse antibiotic resistance in Mycobacterium tuberculosis

March 17, 2017 by Bob Yirka report
This photomicrograph reveals Mycobacterium tuberculosis bacteria using acid-fast Ziehl-Neelsen stain; Magnified 1000 X. The acid-fast stains depend on the ability of mycobacteria to retain dye when treated with mineral acid or an acid-alcohol solution such as the Ziehl-Neelsen, or the Kinyoun stains that are carbolfuchsin methods specific for M. tuberculosis. Credit: public domain

(Medical Xpress)—A team of researchers from Sweden, France, Belgium and Switzerland has found a way to reverse resistance to an antibiotic drug used to treat tuberculosis. In their paper published in the journal Science, the team describes how they screened compounds that activated different pathways to activate ethionaide, a compound used to treat tuberculosis.

The development of antibiotics to treat bacterial infections has very clearly made the world a healthier place. Unfortunately, over time, bacteria have been evolving to thwart such compounds, putting us all at risk once again. Because of that, scientists have been searching for new treatments, or in some cases, ways to make old treatments work again using new techniques. In this new effort, the researchers have found a way to make ethionaide, a prodrug (a compound that is metabolized in the body to produce a desired drug), become effective again in patients infected with of Mycobacterium tuberculosis.

Ethionaide was developed back in the late 1950s as a treatment for tuberculosis. It is activated by an enzyme called EthA found in the bacteria—once activated, ethionaide attacks the bacteria. Over time, many strains of M. tuberculosis have become resistant to ethionaide by developing EthA mutations that do not activate the compound, making it useless as a treatment. To get around this problem, the researchers searched for and found a prototype molecule called SMARt-420 that activates ethionaide by taking a different route—interacting with a secondary gene. The team has found that giving patients a dose of the small molecule after administering a dose of ethionaide restored the lattter's ability to destroy a range of M. tuberculosis—testing showed it reduced the bacterial load found in patient lungs after just three weeks—similar to the effectiveness of ethionaide alone against M. prior to the develop of resistance.

The researchers are currently working with GlaxoSmithKline and Biotech Bioversys to further develop the small prototype molecule into a drug that can be mass produced and sold. They are also looking into the possibility of using the same or a similar technique to overcome resistance to other bacteria.

Explore further: New drug lead identified in fight against tuberculosis

More information: Nicolas Blondiaux et al. Reversion of antibiotic resistance inby spiroisoxazoline SMARt-420, Science (2017). DOI: 10.1126/science.aag1006

Abstract
Antibiotic resistance is one of the biggest threats to human health globally. Alarmingly, multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis have now spread worldwide. Some key antituberculosis antibiotics are prodrugs, for which resistance mechanisms are mainly driven by mutations in the bacterial enzymatic pathway required for their bioactivation. We have developed drug-like molecules that activate a cryptic alternative bioactivation pathway of ethionamide in M. tuberculosis, circumventing the classic activation pathway in which resistance mutations have now been observed. The first-of-its-kind molecule, named SMARt-420 (Small Molecule Aborting Resistance), not only fully reverses ethionamide-acquired resistance and clears ethionamide-resistant infection in mice, it also increases the basal sensitivity of bacteria to ethionamide.

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Nik_2213
not rated yet Mar 17, 2017
Yeah !
I've a long-standing loathing for TB, never mind drug-resistant strains.
A neighbour refused to have his children vaccinated. ( Religious grounds ??) So, when they caught TB on their travels, they infected our district and several of their children's schools. All the affected kids and relatives needed long, long treatment regimes. Each school's students & staff had to be fully tested and vaccinated. My brother and I were lucky, we'd inherited some 'maternal immunity', had enough immune response, were not infected. But, thus primed, our TB 'challenge' flared overnight, went down before inspection. Despite our protests, we were treated as 'No Response', given a full dose of BCG. Our injection sites ulcerated spectacularly. I've still got a scar on my arm...
FredJose
1 / 5 (1) Mar 18, 2017
Good news indeed. One can only hope that more such insights can be brought to play with other infectious agents.

On the other side of the coin, one should note that the resistance is more a result of loss of information - how to digest the poison. This means that there probably was a section of a population that already had the resistance and they simply thrived when the competition got obliterated. The point is that this population did not DEVELOP some new capability as people would like to invoke the word evolution for. Instead it's simply a case of loss of ability because of mutation with a resultant natural selection that made them proliferate.
There is no Darwinian evolution at work here. People should not be fooled by this into believing that "evolution" has occurred. It's just a change in ability to consume poison.
humy
5 / 5 (1) Mar 18, 2017
"...The point is that this population did not DEVELOP some new capability as people would like to invoke the word evolution for. Instead it's simply a case of loss of ability because of mutation with a resultant natural selection that made them proliferate...."
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FredJose

You logically contradict yourself. A mutation for a "loss of ability" that is naturally selected IS evolution just as much as a mutation for a "gain of ability" that is naturally selected i.e. whether it involves a "loss" or "gain" is irrelevant to it being evolution. For example, snakes evolved from reptiles by evolving the "loss" of legs thus "lost of ability" to walk (but gained something by doing that); that is an example of evolution. The essence of evolution i.e. the definition of evolution doesn't involve or have anything to do with whether it involves a "loss" of 'ability' or a "gain" in 'ability', both of which can evolve via evolution. Look up the definition of evolution and then come back to us
humy
5 / 5 (1) Mar 18, 2017
"...It's just a change in ability to consume poison...."
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FredJose

Why not call that "change" a "gain" rather than a "loss"?
It "gain the ability" to consume poison (in the sense that it can consume poison and still continuous to survive) and yet you contradict yourself by asserting;
"Instead it's simply a case of loss of ability";
how can it be the contradiction of BOTH ONLY being a "loss" and yet that "loss" includes that GAIN?

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