According to a new study published online in the early edition of the Proceedings of the National Academy of Sciences, drugs that fight infectious diseases could be designed to block a pathogen’s entry into cells rather than to kill the bug itself.

Traditionally, drugs for infectious diseases were developed to kill the antagonizing pathogen, but according to researchers, this new strategy is important as many parasites and bacteria have the ability to change and circumvent a way around the drugs that target them, resulting in resistance to these drugs.

The new study demonstrated that using an experimental agent to block one type of enzyme in cell cultures and mice blocked a specific parasite from entering white blood cells, which it needs to do in order to cause infection. The researchers’ method focused on pathogens that must enter a host cell in order to survive and do their damage, however some parasites are able to live in a host body outside cell walls.

They decided to test the experimental drug against Leishmania parasites that are transmitted through bites of infected sand flies, causing a parasitic skin infection that is prevalent in tropical and subtropical regions of the world. Worldwide, approximately 1.5 million new cases are diagnosed each year.

Abhay Satoskar, professor of pathology at Ohio State University and senior author of the study explained:

“This represents a new way of thinking about treatment for infectious diseases. This was a proof of concept to see whether this emerging strategy is viable. We aren’t claiming we have a new drug for treatment. If we know this strategy works, then drugs can be developed that target different pathways in the host that could be important for pathogen invasion and survival.”

Leishmania basically operates by hijacking white blood cells of their host. This causes a skin infection known as cutaneous leishmaniasis, which typically causes different-size sores that may or may not be painful.

The standard treatment for Leishmania must be injected and can cause damage to veins as well as other unpleasant symptoms. Patient compliance is poor, because of the side effects and given that infected individuals need daily shots for three weeks, which potentially enables the parasites to develop resistance to the drugs.

Researchers have started to work around pathogens’ abilities to build up resistance to treatment by targeting specific elements of the infection process inside the host body. One of these experimental drugs called AS-605240 targets a specific type of enzyme (PI3K gamma) that becomes activated when white blood cells identify an intruder and the host body starts an immune response.

PI3K gamma manages cell movement and changes to a cell membrane, which allow a pathogen to enter the cell wall. AS-605240 prevents the activity of PI3K gamma, which is subsequently expected to reduce the number of cells recruited to an infection site, allowing few pathogens to enter into the cells that are recruited.

Satoskar and his team conducted a series of tests on animal cell cultures to prove that the PI3K gamma enzyme does indeed control white blood cell activity in the immune response to Leishmania mexicana infection. They also proved that the presence of the experimental agent substantially lowered the parasite’s ability to penetrate white blood cell walls and that it also reduced the number of phagocytes, a type of white blood cell, which were recruited to the infection site. This resulted in fewer opportunities for the parasites to find cells that could serve them as hosts.

When they conducted the same tests in mice, they achieved the same responses with the same results. The researchers then compared mice with Leishmania infection that were treated with AS-605240 with those that receive the current standard drug treatment of sodium stibogluconate. They discovered that the effects in both groups, i.e. the experimental agent and the standard treatment, were very similar at two weeks of treatment. Both therapies reduced the number of parasites within the skin lesions compared with mice that had untreated lesions. The findings revealed that a combination of the treatments achieved stronger healing effects than that of mice that were given only one type of treatment.

Satoskar now wants to modify the strategy and apply it to other host-based pathways that are likely to be safely manipulated in order to prevent pathogens from causing infection. The results of this study indicate that this strategy could not just be used for treatment, but also for prevention.

Satoskar comments:

“There is no prevention for these kinds of diseases. If we had a drug that would reduce the amount of phagocytes coming to the site of infection after parasites enter the skin, which would lead to a less severe infection that the body could probably control on its own.”

He added saying that some people are able to self-heal from a Leishmania infection, however the time-span cannot be predicted and therefore infections are generally treated.

Written by Petra Rattue