Study Confirms New Strategy In Fight Against Infectious Diseases

New research shows that infectious disease-fighting drugs could be designed to block a pathogen’s entry into cells rather than to kill the bug itself.

Historically, medications for infectious diseases have been designed to kill the offending pathogen. This new strategy is important, researchers say, because many parasites and bacteria can eventually mutate their way around drugs that target them, resulting in drug resistance.

In this study, scientists showed that using an experimental agent to block one type of an enzyme in cell cultures and mice prevented a specific parasite from entering white blood cells, a step required for the parasite to cause infection. This method applies to pathogens that must enter a host cell to survive and do their damage. Some bugs can thrive in a host body outside cell walls.

The researchers tested the experimental drug against Leishmania parasites, which are transmitted by the bite of infected sand flies. The pathogen causes a parasitic skin infection common in tropical and subtropical regions of the world, with an estimated 1.5 million new cases diagnosed each year worldwide.

“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,” said Abhay Satoskar, professor of pathology at Ohio State University and senior author of the study. “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.”

The research appears online this week in the early edition of the Proceedings of the National Academy of Sciences.

Leishmania essentially hijacks a host’s white blood cells to cause a skin infection called cutaneous leishmaniasis, characterized by sores of various sizes that may or may not be painful.

The standard compounds used to treat the skin disease must be injected and can cause damage to veins and a host of unpleasant symptoms. The side effects, combined with the need to receive daily shots for three weeks, lead to poor patient compliance – which can then allow the parasites to develop resistance to the drugs.

To work around pathogens’ abilities to circumvent treatment, scientists have begun developing agents that target specific elements of the infection process inside the host body. One such experimental drug is called AS-605240, and it targets one type of an enzyme that is activated when white blood cells recognize an intruder and the host body initiates an immune response.

This enzyme, PI3K gamma, controls cell movement as well as changes to a cell membrane that enable a pathogen to penetrate the cell wall. AS-605240 blocks the activity of the gamma form of the enzyme, which in turn is expected to reduce the number of cells recruited to an infection site and allow few pathogens to enter into the cells that are recruited.