How Do Mycobacteria Evade Rifampicin in the Fight Against TB?
3 November 2024
Researchers combined cryo-EM and advanced biochemical techniques to uncover the role of a key protein in driving antibiotic resistance.
The global fight against antibiotic resistance has taken a promising step forward thanks to new findings from scientists at IOCB Prague, in collaboration with the Institute of Microbiology and the Institute of Biotechnology at the Czech Academy of Sciences. Using cryogenic electron microscopy and advanced biochemical techniques, the team has uncovered a critical resistance mechanism used by mycobacteria to evade the antibiotic rifampicin—a drug commonly used to treat serious infections like tuberculosis and pneumonia.
A protein known as HelD plays a central role in mycobacterial resistance to rifampicin by shielding RNA polymerase, the enzyme essential for the transcription of genetic information, which is vital for bacterial survival. By closely observing HelD’s structure and function, the researchers identified how this protein protects and ‘recycles’ RNA polymerase, allowing the bacterium to continue its growth cycle even in the presence of powerful antibiotics.
“Thanks to advanced cryogenic electron microscope imaging and state-of-the-art biochemical analysis, we have been able to describe in detail how the HelD protein liberates RNA polymerase from the effects of the antibiotic rifampicin,” said Tomáš Kouba, head of the Cryogenic Electron Microscopy scientific group at IOCB Prague.
In practical terms, HelD acts as a protective agent for RNA polymerase, allowing the bacterium to resume transcription of its DNA even under the pressure of antibiotic treatment. During disruptions in the transcription process—such as those caused by rifampicin—HelD steps in to release and reposition RNA polymerase, enabling the continuation of genetic transcription and, thus, bacterial survival and multiplication.
“Modern methods of structural biology have enabled us to observe, at the atomic level, how HelD protects bacteria against the effects of a whole group of antibiotics,” explained Tomáš Kovaľ from the Institute of Biotechnology of the Czech Academy of Sciences. This in-depth understanding is crucial for designing new antibiotics that can circumvent HelD’s protective function.
Previously, scientists suspected that HelD played a significant role in antibiotic resistance, but this study reveals its influence is even broader and more fundamental than anticipated. Not only does HelD counteract rifampicin’s effects, but it also ensures that RNA polymerase can be reused effectively, supporting bacterial function and survival under adverse conditions.
“Understanding the role of the HelD protein is essential for our struggle against antibiotic resistance,” noted Libor Krásný of the Institute of Microbiology. “Thanks to our latest findings, it is possible to deploy new strategies in the search for more effective antibiotic treatments.”
Original Publication:
Kovaľ, T. et al.: Mycobacterial HelD connects RNA polymerase recycling with transcription initiation. Nat Commun (2024); DOI: 10.1038/s41467-024-52891-5
Source: Wiley Analytical Science
