Journal News

JLR: New insights into treating amoebic keratitis

Isha Dey
February 01, 2018

The human body provides a hospitable environment for many micro-organisms that are essential to our survival. At the same time, it also attracts a host of parasites that, if not treated properly or eradicated, can be extremely harmful to our health. One such class of parasite is the infective amoeba, which causes rare and sometimes fatal diseases in humans. The Acanthamoeba species, found worldwide, mostly in water and soil, causes amoebic keratitis, or AK — an eye infection of the cornea that can result in permanent blindness. In the USA, 85 percent of AK cases occur in soft contact lens users. Although AK is potentially life-threatening, its treatment is not yet promising, owing to drug resistance and the absence of species-specific drugs. Hence, we need to identify specific drug targets to better fight these parasites.

Designing species-specific drugs requires an understanding of the unique evolutionary differences among species, especially with respect to biochemical pathways responsible for the survival of the parasite within the host. The Acanthamoeba life cycle has two stages — cyst and trophozoite. The trophozoite is the active form that infects humans, while the cyst is the dormant form that can survive harsh conditions such as stress and lack of nutrients. When conditions become favorable, the cyst transforms to a trophozoite via a process called excystment. Both forms can enter the human body through wounds, nostrils or contact with water.

Electron micrographs show the two stages in the life cycle of Acanthamoeba castellani. Courtesy of the W. David NES labORATORY

Certain metabolic pathways cause the Acanthamoeba to cycle between stages and help the infective trophozoites survive and proliferate in humans. Thus, targeting these specific pathways could prove to be an efficient strategy to treat Acanthamoeba infections. W. David Nes and his group at Texas Tech University have investigated such pathways and reported sterol C24-methyltransferases, or SMTs, synthesized only in amoebae, as novel druggable targets. Their findings were published in the Journal of Lipid Research.

Sterols are amphipathic molecules that, by virtue of their lipid-based properties, act as membrane inserts to control overall growth and development. Ergosterol biosynthesis has been established as essential for the survival of many amoebae in humans, and SMTs are critical enzymes in the ergosterol biosynthesis pathway. SMTs catalyze a crucial step in the ergosterol pathway that maintains trophozoite growth. Interestingly, SMTs are absent in humans. Thus, the researchers found that inhibiting these enzymes with transition-state analogs that blocked the catalytic site on the enzyme, or with suicide substrates that irreversibly bound covalently to the enzyme, stopped the growth of trophozoites but had no effect on normal cholesterol biosynthesis in human cells. So this approach could treat specifically Acanthamoeba infections without harming us. This is the highlight of Nes’ published work.

The work has been quite challenging, especially because differences in sterol biochemistry and life-cycle events among amoeba species make it hard to identify common drug targets. Moreover, Nes’ group required an extensive collaboration to integrate a multidisciplinary approach so as to provide “the most effective drugs, which would escape mechanisms that otherwise could compromise their therapeutic longevity,” Nes said.

Having used keratitis-causing Acanthamoeba castellanii as the model system in their published study, Nes and his group now want to test their hypothesis in mouse models. They also plan to extend their inhibitor studies to Naegleria fowlerii, a “brain-eating amoeba” that can cross the blood-brain barrier and destroy brain tissue, resulting in a disease called primary amoebic meningoencephalitis, or PAM. Further down the road, they hope to develop high-throughput screening techniques to repurpose existing drugs as novel SMT catalysis inhibitors to cure amoebic infections.

Isha DeyIsha Dey is a Ph.D. candidate at Rosalind Franklin University of Medicine and Science.
Isha Dey

Isha Dey is a scientist at Thermo Fisher Scientific in India.

Join the ASBMB Today mailing list

Sign up to get updates on articles, interviews and events.

Latest in Science

Science highlights or most popular articles

Gut microbiome shaped by dietary sphingolipids
Journal News

Gut microbiome shaped by dietary sphingolipids

September 22, 2020

A new tracing method described in the Journal of Lipid Research offers clues on how a macronutrient interacts with the microbes that live inside us.

From the journals: JBC
Journal News

From the journals: JBC

September 21, 2020

Proteases that fire up the flu. A sulfate pocket to take out MRSA. Proteins that prompt cancer protrusions. Read about recent papers on these topics and more.

AeroNabs promise powerful, inhalable protection against COVID-19
News

AeroNabs promise powerful, inhalable protection against COVID-19

September 20, 2020

As the world awaits vaccines to bring the COVID-19 pandemic under control, UC San Francisco scientists have devised a novel approach to halting the spread of SARS-CoV-2, the virus that causes the disease.

Keeping bone and muscle strong on the ISS
News

Keeping bone and muscle strong on the ISS

September 19, 2020

Researchers helped mice stay mighty with an experiment to counter the effects of microgravity. The gene treatment might also enhance muscle and bone health on Earth — and in humans.

Understanding the impact of Type 1 diabetes susceptibility genes
Research Spotlight

Understanding the impact of Type 1 diabetes susceptibility genes

September 17, 2020

Starting in eighth grade, a series of mentors who saw something special in Sharifa Love–Rutledge helped her stay on the path to being a researcher — and becoming a mentor to others.

Re-creating coagulation in a lab
Journal News

Re-creating coagulation in a lab

September 15, 2020

Threatened arthropods are in the crossfire of medical and conservation efforts, but new research could benefit horseshoe crabs and humans alike.