Hebrew U Discovery May Help Ward Off Famine

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Haaretz header - Researchers are seeking regulatory approval for a peptide that can kill bacteria – whether throughout a hospital or inside a milk carton.

A milk carton, a battleground for bacteria.

In the foreseeable future, food companies might be able to store products like milk in miracle containers that kill or at least delay the development of bacteria inside. Experiments are underway at Hebrew University’s Faculty of Agriculture to produce a so-called bioactive milk carton to extend products’ shelf lives.

Of course, this is good news for humanity as a whole. In 2050, the global population is expected to total 9 billion, around 20 percent more than today. But food consumption is expected to surge 70 percent.

So the challenge is there, especially considering the climatic changes that are reducing the supply of arable land and the water available to nurture it.

Slowing down the rotting of food is the basis of research conducted by Dr. Zvi Hayouka of the Institute of Biochemistry, Food Science and Nutrition at Hebrew University’s Rehovot campus. He has collaborated with Dr. Moshe Shemesh of the Volcani Center of agricultural research, Prof. Saul Burdman of Hebrew University’s Department of Plant Pathology and Microbiology, and Prof. David Avnir of the university’s Institute of Chemistry.

To prevent or delay the flourishing of bacteria, Hayouka is using tools developed by nature – antimicrobial peptides. These are short protein chains composed of between 10 and 50 amino acids. The peptides are naturally secreted (as part of the immune system’s efforts) by humans, animals and various plants, all in the aim of preventing infections.

One example is Magainin, which was discovered in 1987 by Prof. Michael Zasloff while he was doing genetic research on frogs. After several years of research, Zasloff was surprised to discover that frogs that had undergone an operation recovered more quickly in the non-sterile environment of an aquarium, without infection or inflammation. Zasloff hypothesized that a frog’s skin secretes some sort of antimicrobial agent.

A few months later, he isolated the substance that was responsible for the frog’s quick recovery – a microbial peptide that he called Magainin (from the Hebrew word magen – shield). Zasloff’s research paved the way to identifying thousands of antimicrobial peptides in the plant and animal kingdoms, including mammals.

Crops at an agricultural community in central Israel.

Like oil and water

According to Hayouka, natural antimicrobial peptides contain amino acids with hydrophobic residues – in other words, they don’t like water. Also present are other amino acids, which carry a positive charge and are capable of “settling” on the membrane of a bacterial cell, which carries a negative charge. After the initial interaction, the peptide undergoes a reversal and the hydrophobic amino acids penetrate the membrane of the bacterial cell, destroying it.

Hayouka’s team developed a new method for the artificial synthesis of random-sequence peptides that are similar to antimicrobial peptides existing in nature. The laboratory-synthesized peptides were quickly effective against numerous bacteria including bacteria that infect food.

These bacteria adhere to moist surfaces found in the food industry and in medical instruments through which fluids flow, like catheters. They create a so-called extracellular matrix, a biofilm. This matrix is composed of proteins, DNA and sugars, and protects the surfaces against antibiotics.

In their research, recently published in the journal Chemical Communications, the scientists showed that the random-sequence peptides can prevent the formation of biofilm and destroy existing biofilm by killing bacteria. These results have numerous potential applications, like on the inner sides of that milk carton mentioned above.

Peptides also have other industrial applications such as hospital disinfectants and the development of food preservatives. In addition, some newly developed antimicrobial peptides serve as pest-control agents sprayed on crops. This development requires relatively complex regulation, partly to show that the active ingredients won’t harm the environment.

“We’re about to launch a project of disinfecting railings, curtains and elevators in a hospital, with the aim of seeing if the materials that we’ve developed are capable of reducing infections that frequently happen in such places,” Hayouka says.

Regulatory hurdle

Won’t the fact that you’re dealing with random sequences of peptides – in other words, a material with a nonuniform structure – get in the way of you receiving approval from the food and drug authorities?

“We’ve shown that the sequence has no influence on the intensity of the peptide’s antimicrobial activity. The fact that a random sequence of peptides can be used offers two important advantages.

“One, the synthesis process of the peptide mixtures is dozens of percentage points less expensive than the cost of creating set sequences. The second advantage is that we can assume that, with random-sequence peptides, it will be harder for bacteria to develop resistance.

“Still, it’s clear that it won’t be easy to receive approval from the food authorities. We have to demonstrate that the activity of the peptides that we’ve identified is selective and specific to membranes of the bacterial cells, and that it doesn’t harm the human cell, for instance, by penetrating and destroying red blood cells.”

Hayouka began his academic research battling a particularly infamous agent: the HIV-1 virus that causes AIDS. As part of his doctoral work at the Hebrew University of Jerusalem, Hayouka joined the laboratory of Prof. Assaf Friedler at the school’s Institute of Chemistry. He was part of a team that developed inhibitors that affected the AIDS virus’ enzyme called integrase.

The virus that causes AIDS has genetic information that it tries to introduce into the host cell’s DNA. When it completes this process, it can replicate within it. Introduction of the virus’ genetic material into the host cell is the critical stage, and integrase is responsible. From this point the disease becomes chronic.

What happened to the project?

“The inhibitors were effective in the test tube in human cells and even in mice, but researchers in Western countries had already developed the drug cocktail that significantly extends the life of patients, meaning we arrived too late. Still, we got a patent on our development, and a pharmaceutical company recently expressed an interest in it.”

If the Western world feels that the disease is under control, what would make this company interested in your work?

“The AIDS virus is sophisticated, and it’s only a matter of time until it develops a resistance to the drug cocktail. This has also happened in antibiotics, in which there wasn’t an investment in the development of new drugs. So now we’re dealing with a serious crisis due to the reduced effectiveness of the old generation of antibiotics.”

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CFHU is dedicated to supporting IMRIC through direct funding and by developing key collaborative medical research partnerships between Canada
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