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How tetracycline antibiotics impair T cell function by targeting mitochondria

A team of international researchers led by Karolinska Institutet has revealed in unprecedented detail how tetracycline antibiotics impair T cell function by binding mitochondrial ribosomes and inhibiting oxidative metabolism (OXPHOS). The , reported in Nature Communications, raises mechanistic considerations for antibiotic therapy and the design of new molecules that can better discriminate between pathogen and host.

Numerous studies have shown how the electron transport chain (ETC) influences both innate and adaptive immune mechanisms. For example, bouts of OXPHOS upregulation are required during lymphocyte development, activation, and maturation.

More effective use of antibiotic therapy

Antibiotics historically developed to inhibit bacterial protein synthesis cross-react with mitochondrial ribosomes due to shared evolutionary features, impairing translation of key phosphorylation complex subunits in host cells. Indeed, certain antibiotics, such as tetracyclines, have a long history in the treatment of inflammatory conditions, such as rheumatoid arthritis, although large controlled cohort studies are lacking, in part due to the lack of a molecular mechanism.

"When you take antibiotics, the effects are not solely restricted to commensal and pathogenic bacteria. Some of your cells take a hit, and there is good evidence in the literature to support reversible inhibition of that mitochondrial translation can be used to treat inflammatory diseases," explains Xaquin Castro Dopico, research specialist at the Department of Microbiology, Tumor and Cell Biology at Karolinska Institutet and one of the study's lead authors.

Future directions

The researchers identified specific structural features of mitochondrial ribosomes that could potentially be targeted to develop more selective therapeutics.

"The discrimination between bacterial and human mitochondrial ribosomes represents an important frontier for antibiotic development. By understanding the specific binding domains within the mitoribosome that interact with tigecycline, it will be possible to design next-generation entities with different specificities, whether those affect the host or pathogen," says Dr. Joanna Rorbach, principal researcher at the Department of Medical Biochemistry and Biophysics at Karolinska Institutet.