Antibiotics against viruses

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Antibiotics block bacterial growth and are routinely prescribed to patients suffering from bacterial infections. They do not help against viruses. So somewhat surprisingly headlines like “An already in-use antibiotic may limit Zika infections” have been hitting the news recently. But how exactly do antibiotics affect viruses?

Blocking the infection of cells

In order to replicate, viruses need to infect (=enter) cells. A study by UCSF researchers published in PNAS in December 2016, identified a molecule, called AXL, expressed on the surface of different cell types as susceptibility factor for Zika infection. AXL, which is highly expressed on neural stem cells as well as brain immune cells is an entry point for the virus making these cells more likely to be infected. Neurons, which express lower levels of AXL, are less prone to Zika infections. Reducing AXL expression in glia cells, using genetic knock out models (CRISPR) or blocking antibodies, decreased Zika infection rates in these glia cells.

Aiming to find already in-use medications that can block Zika virus dependent cell death, the researcher performed a Small Molecule Discovery Screen. In this assay they tested the effect of 2177 FDA-approved drugs on cell lines. Several of the tested compounds rescued cell viability – including the antibiotic azithromycin (AZ). Subsequent tests showed that AZ can block Zika-mediated cell death in human astrocytes as well decrease virus proliferation.

How can an antibiotic effect Zika?

AZ is normally used to treat middle ear, throat or sexually transmitted infections caused by bacteria. It is safe to take during pregnancy – which is a key feature if the drug is to be used for Zika infections in mothers-to-be.  AZ normally blocks bacterial growth by interfering with protein synthesis. The antibiotic binds the 50S subunit of the bacterial ribosome and thereby inhibiting mRNA translation. The binding and blocking of the 50S ribosomal subunit is specific for the bacterial ribosome. Human (or all eukaryotic for that matter) ribosomes contain different subunits and aren’t susceptible to antibiotics.

Viruses, unlike bacteria, do not have their own protein synthesis machinery. They infect cells and utilize the host ribosomes to produce viral proteins – which is why antibiotics can not affect viruses. At least not in their classical mode of action. What this studies shows is a non-classical function besides blocking of ribosomes. AZ somehow inhibits Zika, maybe by blocking Zika and AXL interactions. This remains to be proven thou.

The data in this study is mainly derived from cell culture experiments; it is therefore unclear if AZ will have the same protective effect in humans. Previous studies on AZ have shown that the antibiotic can enter the placenta and fetal tissues, suggesting it may have a good chance at blocking Zika in humans. A clinical trial to test this is currently being initiated in Brazil.

Not just one antibiotic can help prevent Zika

This hasn’t been the first paper showing that an antibiotic may help against Zika. A study published in July 2016, found that duramycin can block the infection of placental cells and thereby the transmission of the virus from mother to fetus. A molecule called TIM1 was identified susceptibility factor in placental cells – similar to AXL in the brain.

Taken together, this new data teaches us to have a second look at antibiotics. Even though in neither case it is known how the antibiotics prevent Zika infection (maybe by blocking Zika from binding AXL/TIM1, but this remains to be proven) – it appears antibiotics are not restricted to fighting bacteria.

Picture of the mosquito from flickr;  licence: CC BY 2.0

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