Tetracycline antibiotics show promise against Zika virus

Having screened more than 10,000 compounds, researchers have found that the widely used antibiotic methacycline can prevent Zika virus brain infections and reduce the resulting neurological problems associated with the virus in mice. They also identified two other potential drug candidates but suggested that methacycline was the most promising, since it is widely available and already approved by many regulators.

In 2015, hundreds of children were born with brain deformities because of the global Zika virus outbreak. More than 60 countries reported Zika virus infections in 2015 and 2016. Some also reported a high incidence of infected mothers giving birth to babies born with abnormally small heads resulting from a developmental brain disorder called foetal microcephaly. Adults also experienced neurological symptoms as a result of Zika virus, these included Guillain-Barré syndrome, encephalitis and myelitis.

Unfortunately, despite research efforts, scientists have yet to discover an effective treatment or vaccination for the virus.

In a new study published in PNAS, researchers screened libraries of known drugs for candidates that may be able to prevent the virus from reproducing by blocking the NS2B-NS3 Zika virus protease. The NS2B-NS3 protease is essential for Zika virus replication – it cleaves proteins produced by the host cells’ translation machinery into the correct components for viral assembly.

To identify potential candidates, the scientists first created assays that could assess the ability of drugs to inhibit NS2B-NS3 protease activity in plates containing hundreds of tiny test tubes. Each assay was tailored to a different screening technique and used to simultaneously evaluate thousands of candidates stored in three separate libraries.

One preliminary screen of 2,000 compounds suggested that commonly used, tetracycline-based antibiotic drugs such as methacycline may be effective at blocking the protease. A larger screen of 10,000 compounds also suggested an investigational anti-inflammatory medicine called MK-591 and a failed Alzheimer’s drug, called JNJ-404, could be potential candidates. A virtual screen of over 130,000 compounds was also used.

According to the team, the Zika virus preferentially infects stem cells in the brain. Many believe this is why infections cause more harm to developing foetuses than to adults. In their study, the researchers validated the results of their drug screens in in vitro neural stem cell cultures. They reported that treating the cells with methacycline, MK-591 or JNJ-404 reduced Zika virus infections.

Because tetracyclines are US Food and Drug Administration (FDA)-approved drugs that are known to cross the placenta, the researchers focused on methacycline and found that it may reduce some neurodevelopmental problems caused by the Zika virus. In their study, newborn mice treated with methacycline had better balance and could turn over more easily than ones that were given a placebo. Examinations of their brains suggested this was because the antibiotic reduced infections and neural damage. Nevertheless, the antibiotics did not completely counteract harm caused by the Zika virus, the weight of treated mice was still lower than control mice.

“Around the world, the Zika outbreak produced devastating, long-term neurological problems for many children and their families. Although the infections are down, the threat remains,” said Dr Avindra Nath, senior investigator at the US National Institute of Neurological Disorders and Stroke (NINDS) and a senior author of the study. “We hope these promising results are a good first step to preparing the world for combating the next potential outbreak.”

Dr Rachel Abrams, an organic chemist in Nath’s lab and the study leader, concluded: “These results suggest that tetracycline-based antibiotics may at least be effective at preventing the neurological problems associated with Zika virus infections. Given that they are widely used, we hope that we can rapidly test their potential in clinical trials.”