Centre of Molecular Structure
Scientists describe how bacteria evade the effects of antibiotics
One of the main challenges of contemporary medicine is posed by the resistance of pathogens to antibiotics. An important step in countering it has now been made by researchers from IOCB Prague, in collaboration with colleagues from the Institute of Microbiology and the Institute of Biotechnology of the Czech Academy of Sciences. Leveraging advanced cryogenic electron microscopy and biochemical methods, they have managed to describe how mycobacteria defend themselves against the antibiotic rifampicin. Their latest study on the matter has been published in the scientific journal Nature Communications.
One key component that allows a bacterium to dodge the action of the antibiotic rifampicin is a protein called HelD. It effectively protects bacterial RNA polymerase, which is the enzyme taking care of the transcription of genetic information from DNA to RNA, a process that is crucial for the survival of all bacteria.
“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,” says Dr. Tomáš Kouba, who leads the Cryogenic Electron Microscopy scientific group at IOCB Prague.
Model of the RNA polymerase and HelD protein complex. Using biochemical analysis and cryogenic electron microscopy, the researchers showed how HelD actively counteracts the presence of rifiampicin in RNA polymerase and prevents the action of the antibiotic.
The HelD protein acts as a cellular bodyguard. Whenever there's a snag during the transcription of DNA, HelD comes to the rescue, and this is also what happens after the administration of rifampicin, the role of which is to inhibit RNA polymerase. Without HelD, the whole process would grind to a halt and the bacterium would perish. HelD does not yield even to such a powerful antibiotic as rifampicin, which is used, for example, to treat tuberculosis or severe pneumonia.
“Modern methods of structural biology have enabled us to observe, at the atomic level, how HelD protects bacteria against the effects a whole group of antibiotics,” says Dr. Tomáš Kovaľ from the Laboratory of the Structure and Function of Biomolecules at the Institute of Biotechnology of the Czech Academy of Sciences.
Until recently, researchers had assumed that HelD played a crucial role in antibiotic resistance. However, they have found that it is even more important for bacteria than it seemed. The HelD protein not only sets RNA polymerase free from the effects of the antibiotic but also ensures the ‘recycling’ of this enzyme, which is crucial for the functioning of every organism. It achieves this by actually moving RNA polymerase to the transcription initiation site on DNA, allowing it to resume transcription. The bacterium can thus start multiplying again.
"Understanding the role of the HelD protein is essential for our struggle against antibiotic resistance," explains Dr. Libor Krásný, who leads a research group at the Institute of Microbiology of the Czech Academy of Sciences, adding that "Thanks to our latest findings, it is possible to deploy new strategies in the search for more effective antibiotic treatments."
Antibiotic resistance is a worsening global problem, and the world's most prominent research institutions are focusing on finding weak points in how bacteria evade treatment.
Original article: Kovaľ, T.; Borah, N.; Sudzinová, P.; Brezovská, B.; Šanderová, H.; Vaňková Hausnerová, V.; Křenková, A.; Hubálek, M.; Trundová, M.; Adámková, K.; Dušková, J.; Schwarz, M.; Wiedermannová, J.; Dohnálek, J.; Krásný, L.; Kouba, T. Mycobacterial HelD connects RNA polymerase recycling with transcription initiation. Nat. Commun. 2024, 15, 8740. https://doi.org/10.1038/s41467-024-52891-5
