Antibiotics make a double play

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Science Translational Medicine  21 Oct 2020:
Vol. 12, Issue 566, eabe9218
DOI: 10.1126/scitranslmed.abe9218


In addition to antibacterial activity, tetracycline antibiotics induce disease tolerance by altering host mitochondrial function.

Department of Obstetrics & Gynecology, Center for Reproductive Health Sciences, Washington University School of Medicine, BJC Institute of Health, St. Louis, MO 63110, USA. Email: kommagani@wustl.edu

In response to infections, the host deploys the innate immune system to sense the type of pathogen, estimate the extent of the threat, and then react through complex effector responses to neutralize or eliminate the invading microbes. This defense mechanism is sometimes inadequate, leading to sepsis and a strong inflammatory response. In such cases, clinicians treat patients with antibiotics to kill the bacteria. However, this is often insufficient, as many sepsis patients die in spite of having eradicated the pathogen. Thus, there is a critical need of pharmacological treatments that can limit the cellular damage caused by bacteria and the host immune response. New research from Colaço et al. reveal that one old drug, the tetracycline-class antibiotic doxycycline, can do just that.

In this paper, the investigators first generated a mouse model of sepsis by intraperitoneally injecting mice with tetracycline-resistant Escherichia coli. They then treated the animals with low-dose doxycycline and found that, despite no reduction in bacterial load, the mice were much more likely to survive than mice that received phosphate-buffered saline (controls). Colaço et al. further showed that the mice that received doxycycline had less lung and liver damage than controls. In the liver, doxycycline-treated animals had less lipid accumulation and improved fatty acid oxidation and responses to glucocorticoids. Finally, they explored the molecular mechanisms of this antibiotic-induced tolerance and found that doxycycline promoted temporary changes to mitochondrial electron transport. These changes seem to be key to tolerance, as treatment with phenformin, a known inhibitor of complex I of the electron transport chain, conferred a strong survival advantage in septic mice. Together, these findings suggest that, just as a talented baseball team can make two outs during the same play, tetracycline antibiotics can kill both bacteria and alter host mitochondrial electron transport to reduce organ damage.

This study suggests that disease tolerance–based therapies could be developed to improve sepsis treatment and save lives. One key limitation of this study is that the relative contributions of antibacterial activity and tolerance actions of doxycycline in protecting against sepsis were not examined. Additionally, the long-term impact on the liver and other organs of perturbing electron transport was not described. Nonetheless, this work should set the stage for future investigations into other antibiotics that may alter host physiology and promote tolerance. In the long term, such work could lead to development of new classes of drugs that could be combined with antibiotics to treat or prevent sepsis.

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