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Towards designing less-toxic antibiotics

Mitochondria are essential organelles found in every human cell, required to convert food into usable energy. Mitochondria possess their own genome that is central to their function. Proteins encoded by this genome are produced by specialised large complexes called mitoribosomes. As mitochondrial energy metabolism is a foundation for health, even subtle defect in mitochondrial function can cause pathologies. Aminoglycosides, which target bacterial protein production, are one of the most common antibiotics globally, however, they may cause significant toxicity effects, resulting in irreversible hearing loss. Moreover, it is known that patients with mutations in mitochondrial genome are more susceptible to aminoglycosides. Importantly, several other antibiotics that inhibit bacterial protein production also have adverse effect on mitochondrial function, but their pathogenetic mechanisms are not understood.
As mitoribosomes are categorized as a bacteria-type ribosomes, it is likely that several classes of antibacterial compounds directly bind to the mitoribosome and inhibit protein production. Indeed, we have recently shown that some antibiotics, including streptomycin bind to human mitoribosomes.
The objective of this project is to investigate the molecular basis for antibiotic susceptibility of mitoribosomes. I plan to employ innovative methods to characterize interactions of antibiotics with mitoribosomes in unprecedented detail. Analysis of the mitoribosomes captured with antimicrobial therapeutics will provide useful information for the rational design of new drugs having less adverse effects in humans and animals.


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Related publications

Journal Article

Yuzuru Itoh, Aas Khawaja, Vivek Sight, Andreas Naschberger, Joanna Rorbach, Alexey Amunts. 2023. Structural basis of streptomycin off-target binding to human mitoribosome. ELife, 8(11), e77460.

Journal Article

Krüger, Annika, Cristina Remes, Dmitrii Igorevich Shiriaev, Yong Liu, Henrik Spåhr, Rolf Wibom, Ilian Atanassov, Minh Duc Nguyen, Barry S. Cooperman and Joanna Rorbach. 2023. Human mitochondria require mtRF1 for translation termination at non-canonical stop codons. Nature Communications, 14(1), 30.

Journal Article

Remes, Cristina Remes, Anas Khawaja, Sarah F. Pearce, Adam M. Dinan, Shreekara Gopalakrishna, Miriam Cipullo, Vasileios Kyriakidis, Jingdian Zhang, Xaquin Castro Dopico, Olessya Yukhnovets, Ilian Atanassov, Andrew E. Firth, Barry Cooperman and Joanna Rorbach. 2023. Translation initiation of leaderless and polycistronic transcripts in mammalian mitochondria. Nucleic Acids Research.

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Is any information on this page incorrect or outdated? Please notify Ms. Nel-Mari Loock at [email protected].