Recipient organisationNewcastle UniversitySource-published name: Newcastle University
Funding£464K
PeriodApr 2025 — Apr 2028
In plain English
AI plain-English summary
When mycobacteria run out of oxygen, a newly discovered protein physically pins their protein-making ribosomes to the inner cell membrane, locking them into a dormant state that keeps the bacteria alive for months. This matters because mycobacteria—the family that includes the pathogen causing tuberculosis—survive harsh conditions by entering a non-growing, persistent state that is notoriously difficult to treat. Current antibiotics mostly kill actively dividing cells, leaving dormant bacteria to reawaken later. Exactly how mycobacteria shut down and preserve their ribosomes during stress has been poorly understood, and many hibernation factors remain unknown. The researchers will use cryo-electron microscopy to map the 3D structure of this new hibernation factor bound to the ribosome, test how mutant bacteria lacking the factor fare under low-oxygen conditions, and search across bacterial species to see whether this membrane-tethering strategy is widespread or unique to mycobacteria. This is fundamental science with no immediate practical application. But understanding how mycobacteria enforce dormancy could eventually point toward drugs that prevent them from entering persistence in the first place—or that force them out of hiding so existing antibiotics can work.
View original technical description
To endure starvation and stress, bacterial cells employ a specialised class of proteins known as ribosome hibernation factors. These protective proteins prevent undesired activity and degradation of ribosomes in metabolically inactive cells, which helps bacteria to retain their viability and rapidly recover when conditions improve. While hibernation factors are indispensable for long-term stress survival, they are not universally conserved across species, and the total number of such factors in nature remains unknown. In our preliminary work supporting this application, we have identified a novel ribosome hibernation factor. We also showed that this protein appears to anchor ribosomes to the inner cell membranes in hypoxic mycobacteria. In this application, we will develop this study and achieve the following specific aims. Firstly, we will determine the cryo-EM structure of the protein bound to the ribosome to provide the structural basis for its activity. Secondly, we will use our knockout strains of Mycobacterium smegmatis to assess the impact of this factor on mycobacteria's ability to preserve ribosomes and survive hypoxia. Lastly, we will determine the evolutionary conservation of this factor across bacteria to assess if a similar mechanism of ribosome hibernation is widely employed or specific to mycobacterial species. Overall, this study will advance our fundamental understanding of how mycobacteria endure hypoxia through entering persistence, which may contribute to the development of future medical interventions against mycobacterial infections.
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