Tuberculosis bacteria halt their growth with self-toxins that could inspire novel therapeutics
Stealthy bacteria slow down their division when they invade the body to avoid drawing the immune system’s attention. Mycobacterium tuberculosis, the world’s leading bacterial infectious killer, takes a seemingly counterintuitive approach to that end. M. tuberculosis expresses self-toxins that damage its DNA and shut down growth as well as antitoxins to later help recuperate and resume proliferation. By studying these toxin-antitoxin pairs, Durham University microbiologist Professor Tim Blower aims to find ways to mimic the self-toxins with new therapeutics
By conducting X-ray crystallography at Diamond’s I04 beamline, Blower and his colleagues uncovered the structure of toxin-antitoxin complexes, providing insight into how they regulate DNA damaging activity. The findings reveal that the protein pair potentially form two types of complexes. A grouping of two toxins and four antitoxins dominated at body temperature, whereas an equal pairing of two and two were more common in colder conditions, which may reflect how the proteins come together when bacteria live in the environment. These findings change our perspective on how the toxins and antitoxins operate, bringing researchers closer to designing new drugs against a pandemic microbe that continuously evolves resistance to existing antibiotics.
Each year, Mycobacterium tuberculosis leads approximately 10 million people to endure a bloody cough, exhaustion, and fever, and it causes over one million deaths. Doctors typically prescribe patients a course of four to six antibiotics to clear the infection, but the bacteria evolve mechanisms to resist the effects of the drugs. As many as 2.5 percent of tuberculosis patients carry variants of the bacteria resistant to the four most common first-line antibiotics, and that proportion is expected to climb if researchers don’t develop other therapeutics that could kill resistant strains.
Poison control
Blower and the team from Durham University and Newcastle University study mechanisms the bacteria use to limit their own growth in pursuit of inspiration for new drug candidates. Specifically, they focus on an enzyme that controls DNA organisation in the cell and a pair of toxins and antitoxins that regulate this enzyme’s function.
Bacteria and eukaryotes (for instance, humans), organise DNA in the cell differently. Eukaryotic DNA is tightly packaged in the nucleus by histone proteins that wind it up into compact chromosomes. Bacteria, on the other hand, lack histones and rely on DNA to undergo a process called supercoiling. Like how a wound-up rubber band contracts into a small volume, bacterial DNA winds up into a condensed coil to save space. However, supercoiled DNA needs constant maintenance, which involves occasional unwinding and rewinding of the molecules. To this end, an essential enzyme called DNA gyrase cuts the DNA, allows it to untwist, and glues the cut ends back together again, so they can coil again.
Repairing the DNA breaks is essential to the bacteria’s survival because it avoids the build-up of harmful DNA damage and mutations, but sometimes M. tuberculosis interferes with the process. It achieves this using a toxin-antitoxin system that inhibits DNA gyrase. Scientists are still uncertain about the biological role of the toxin, Blower said, but one hypothesis is that by partially shutting down bacterial growth, it prevents antibiotics that target growth machinery from working. Another is that the toxin helps quiescent bacteria evade immune detection as slow-growing microbes tend to slip under the radar. The antitoxin relieves the bacteria, allowing those that survived the accumulation of DNA breaks to seal them back together and resume growth when conditions in the body become favourable.
Researchers developing new therapeutics are drawn to these systems. Suggesting scientists could develop copycat drugs, Professor Blower said:
If these toxins are so effective at killing, then we should take advice from nature and work out how they work.
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