Tetracyclines: four rings to rule infections through resistance and disease tolerance
Kátia Jesus, Luís F. Moita
Kátia Jesus, Luís F. Moita
Published September 1, 2022
Citation Information: J Clin Invest. 2022;132(17):e162331. https://doi.org/10.1172/JCI162331.
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Commentary

Tetracyclines: four rings to rule infections through resistance and disease tolerance

Abstract

Several classes of antibiotics have long been known for protective properties that cannot be explained through their direct antimicrobial effects. However, the molecular bases of these beneficial roles have been elusive. In this issue of the JCI, Mottis et al. report that tetracyclines induced disease tolerance against influenza virus infection, expanding their protection potential beyond resistance and disease tolerance against bacterial infections. The authors dissociated tetracycline’s disease-resistance properties from its disease-tolerance properties by identifying potent tetracycline derivatives with minimal antimicrobial activity but increased capacity to induce an adaptive mitochondrial stress response that initiated disease tolerance mechanisms. These findings have potential clinical applications in viral infections.

Authors

Kátia Jesus, Luís F. Moita

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Figure 1

Tetracycline derivatives with minimal antimicrobial activity have increased capacity to induce an adaptive mitochondrial stress response and enhance disease tolerance.

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Tetracycline derivatives with minimal antimicrobial activity have increa...
(A) Doxycycline, a prototypical tetracycline antibiotic, blocks bacterial and mitochondrial translation, inducing mild proteotoxic mitochondrial stress, which initiates mitochondrial stress responses. (B) 9-tert-Butyl doxycycline (9-TB), a doxycycline derivative with a substitution at the C9 position, has minimal antimicrobial activity but shows substantially greater capacity to induce the UPRmt and mitochondrial stress response (MSR) when compared with parental doxycycline. (C) Mottis et al. (17) showed that both parental doxycycline and 9-TB improved survival of mice in a model of lethal influenza virus infection, by reducing tissue damage but without affecting viral titers. This finding demonstrates that in addition to the antimicrobial properties of tetracyclines (known as resistance), the effect of this class of antibiotics on the host mitochondria triggers disease tolerance mechanisms in viral infections through activation of MSRs.