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Saskia v. Popescu, MPH, MA, CIC, is a hospital epidemiologist and infection preventionist with Phoenix Children's Hospital. During her work as an infection preventionist she performed surveillance for infectious diseases, preparedness, and Ebola-response practices. She is currently a PhD candidate in Biodefense at George Mason University where her research focuses on the role of infection prevention in facilitating global health security efforts. She is certified in Infection Control.

Estrogen Receptor Modulators Could Tackle Infectious Diseases

JAN 08, 2019 | SASKIA V. POPESCU
The research and development of new drugs can be extremely expensive and take years, or even decades to complete. The process of drug discovery, especially for infectious diseases, is so costly and time-consuming that many pharmaceutical companies do not see them as particularly profitable. In fact, one of the challenges clinicians face in fighting antimicrobial resistance is a lack of novel antimicrobials. Fighting infectious diseases can be especially challenging and the pursuit of medical countermeasures is always a priority.
     
What if we could use existing medications to fight infectious diseases? For example, thalidomide—which was created as a sedative and anti-nausea medication during pregnancy but was quickly pulled from the market because it caused birth defects—was repurposed when scientists found that it had anti-inflammatory properties and could treat side effects and complications associated with leprosy, as well as myeloma.

Investigators on a new study have thrown their hat into the ring in this effort to repurpose already approved medications by exploring how estrogen receptor antagonists could be utilized for infectious disease treatments. They evaluated the triphenylethylene class of estrogen receptor modulators related to tamoxifen (ie, tamoxifen, clomiphene/clomifene, and raloxifene) as a potential agent against bacteria, fungi, parasites, and viruses.
   
Tamoxifen has shown analogs effective against HIV, Ebola, hepatitis C, Candida spp, Mycobacterium tuberculosisStaphylococcus aureus, and more. The antifungal activity of tamoxifen has been documented since the 1980s, while studies exploring its antiviral activities have gone back to the 1990s. Investigators reviewed these studies to assess just how much power tamoxifen could offer against infectious diseases. They found that antimalaria activity of tamoxifen and clomiphene was investigated in vitro and study results showed that parasitic growth was inhibited by 80%.

In addition, the investigators found that the process of repurposing triphenylethylene molecules as an antibacterial has strong potential for future research. Initial drug screening, which is required by the US Food and Drug Administration (FDA) for approved drugs, identified antibacterial activity in triphenylethylene molecules in 2013. This screen was for FDA-approved drugs that caused lysis in certain pathogens, such as “Enterococcus faeciumS aureusKlebsiella pneumoniaeAcinetobacter baumanniiPseudomonas aeruginosa, and Escherichia coli. Tamoxifen and clomiphene showed bacteriolytic effects against planktonic E faecium and A baumannii,” according to the investigators. Furthermore, in vitro studies showed that using tamoxifen with current anti-tuberculosis drugs helped enhance growth.

Since this field is still new, there is much more research needing to be done, but the thought is that tamoxifen might have the potential to disrupt the membrane of bacteria, which would inhibit growth. The authors encouraged additional studies to apply these findings to real-world treatment options.  
   
Overall, tamoxifen, clomiphene/clomifene, and raloxifene, showed considerable in vitro activity against bacteria like A baumannii, viruses like Ebola, and even fungi like Candida spp, among others. The team did not find as many in vivo studies, and so the activity levels for those drugs against infectious diseases were not as well documented, but there was some activity against Ebola and Leishmania spp.

Overall, this study gives insight into the potential for tamoxifen and other estrogen receptor antagonists against infectious diseases. There is certainly promise in drug repurposing and as the need for anti-infectives grows due to increasing infectious disease threats, these strategies will be critical.  
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Big advances in treatment can't make up for an inability to stop new infections, which number 5,000 per day worldwide.
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