Tuberculosis: ‘Suicide’ toxin–antitoxin system identified as a drug target


Researchers have investigated a toxin–antitoxin system in tuberculosis as a therapeutic target, providing the first high-resolution details.

Tuberculosis contains 80 toxin–antitoxin systems (TAs); sets of closely linked genes that encode a toxic protein and an antitoxin. When the bacteria are growing normally the toxin’s activity is blocked by the antitoxin’s presence. However, under stressful conditions the antitoxin molecules are degraded, activating the toxin and slowing the growth of the bacteria, allowing them to survive the stressful environment.

The researchers identified one TA, termed MbcT, with a more dramatic effect – in the absence of the antitoxin the toxin kills the bacteria. This effect flagged MbcT’s potential as a drug target and led the team, headed by Annabel Parret, staff scientist at the European Molecular Biology Laboratory (Hamburg, Germany), to try and understand its structure. Parret commented: “Our goal was to see the TA system’s structure, so we could try to understand and even manipulate it. It was as if we were working blindly before.”

The high-resolution structure revealed a large and compact system with a double doughnut shape, and this knowledge gave important guidance for further studying the system’s biochemistry. The researchers were able to understand MbcT’s mode-of-action; without the antitoxin, the toxin starts to degrade the important cellular molecule NAD+, a ‘suicide’ mechanisms ultimately leading to the death of the cell.

“Our collaborators in Toulouse (France) were already able to extend the lifetime of mice infected with TB by activating the toxin in a controlled way,” commented Parret. “If we find molecules that can disrupt the TA system – and thus trigger cell death –  in TB patients, that would be the perfect drug.”

The team now hopes to screen small molecules for this capability, and identify a potential drug target.

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