Drugs for infectious diseases have so far been designed to kill the bug itself. However a study published online in Proceedings of the National Academy of Sciences reveals that these medications could be designed to obstruct the pathogen’s entry into cells instead.

According to the investigators, this new approach is important as several bacteria and parasites can become resistant to medications that target them.

The team used an investigational agent to prevent one type of an enzyme in cell cultures and mice. This agent blocked a specific parasite from invading white blood cells, an action required in order for the parasite to cause infection. In addition, this approach applies to pathogens that need to invade a host cell in order to survive and cause damage.

The investigators tested the experimental drug against Leishmania parasites. These parasites are transmitted by the bite of a certain species of sand fly and take over a host’s white blood cells and cause a skin infection – cutaneous leishmaniasis – which is characterized by skin sores of various sizes.

This skin infection is prevalent in subtropical and tropical regions of the world. Each year it is estimated that 1.5 million individuals are infected by these parasites worldwide.

Abhay Satoskar, professor of pathology at Ohio State University and senior author of the investigation explains:

“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.”

Currently, drugs used to treat the skin disease must be injected daily for three weeks and can cause damage to veins. In addition the medication can cause a variety of adverse effects. Combined the injections and adverse effects can result in poor patient compliance, which can then lead to the parasites developing resistance against medications.

Agents that target specific elements of the infection process inside the host body have started being developed by researchers in order to work around the pathogen’s abilities to develop resistance against treatment.

One investigational drug called AS-605240 targets the P13K gamma enzyme that is stimulated when white blood cells detect an invader and the host body initiates an immune response.

P13K regulates cell movement and alterations to a cell membrane that allows a pathogen to enter the cell wall. AS-605240 is designed to prevent the activity of P13K.

The team conducted a series of tests on animal cell cultures to show that P13K controls white blood cell activity in the immune response to Leishmania mexicana infection and that AS-605240 considerably reduces the parasites ability to enter white blood cell walls.

Furthermore, the researchers discovered that AS-605240 reduced the number of phagocytes (one type of white blood cell), meaning the parasites had less chances of finding cells they could enter.

These experiments were then conducted in mice, with the same results. The team then compared the current standard drug treatment, sodium stibogluconate with AS-605240 treatment of Leishmania infection in mice.

The team found that after two weeks of treatment, both the standard treatment and the investigational treatment produced very similar effects, and both lowered the number of parasites within skin lesions than untreated lesions. In mice who received both treatments the effects were stronger than in mice that received just one type of treatment.

Satoskar plans to fine-tune the approach as well as consider additional host-based pathways to prevent parasites from causing infection. Results from the study indicate that such a strategy could but used for both treatment and prevention.

Satoskar explained:

“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, that would lead to less severe infection that the body could probably control on its own.

Some people can self-heal from a Leishmania infection, but the time it takes is unpredictable so infections are typically treated.”

The study received funding from the National Institutes of Health.

Written by Grace Rattue