Ben-Gurion U. researchers hit back at antibiotic-resistant infections
The World Health Organisation (WHO) has estimated that there could be 10 million deaths per year by 2050 because of drug-resistant infections.
The fight against drug-resistant bacteria is on. Antibiotic-resistant infections are increasingly becoming a significant problem in both hospitals and the community.
But, BGN Technologies, the technology company of Ben-Gurion University of the Negev, has introduced a novel method developed by researchers for screening and detecting new antibiotics, which aims to change this status quo.
“The ribosome, the protein-manufacturing machinery of all living cells, is one of the main targets of antibiotics,” BGN said Monday. “Inhibition of ribosomal activity in bacterial cells results in depletion of essential proteins and finally in cell death.”
However, the university pointed out, “the ribosome is a huge complex, containing both RNA molecules and several proteins, therefore identifying drugs that will inhibit its activity is a challenging task.”
Dr. Barak Akabayov, from the Department of Chemistry at BGU, and his team, have developed a method to design new antibiotics that target a small RNA region in the ribosome, which is called the peptidyl transferase center (PTC).
Focusing on this region allows quick and efficient drug screening and drug design.
Speaking to The Jerusalem Post, Akabayov said the new method takes advantage of two facts.
“Many antibiotics known to date target the bacterial ribosome, [which is] the machinery that manufactures proteins for the living cell, and you can often predict the function of a large molecule if you understand the activity of a small portion in it,” he said, adding that “you can call it the ‘active’ region of the molecule.”
Akabayov said that much like in a key, “the important part is the small region that goes into the keyhole, and the rest of the key can have many shapes.”
What the researchers did was first find empirically small molecular fragments that bind to a specific region of the ribosome and inhibit its activity.
“These fragments are too small to constitute a drug,” Akabayov noted.
“Then they digitally searched a huge database of larger molecules and looked for those that contain the small fragments that were shown to inhibit the ribosome, with the hope that the large molecule would also inhibit the ribosomal activity,” Akabayov explained.
He said this led them to find two such large molecules that can function as novel antibiotics.
Akabayov’s screening and computational chemistry approach combines tools from different disciplines in drug development that bypass many of the limitations of current drug discovery in terms of cost and time.
“This method enables the isolation of inhibitors against targeted pathways that cannot be adapted for high throughput screening and therefore are considered as ‘non-drug’ targets,” he said. “This platform serves as the basis for the development of inhibitors targeting any biochemical pathway.”
Asked if this approach will change the way antibiotics are developed in the future, Akabayov said their method bypasses many of the limitations of current drug discovery in terms of cost and time and increases the chances of success.
“These advantages over the standard methods can increase the number of lead molecules that can eventually be developed into a drug,” he said. “With the use of computational tools, the molecular design of the drug candidate is now more accurate and flexible, for example [it is] applicable to many targets.”
With drug-resistant infections killing 700,000 people worldwide each year and without new therapies, the World Health Organization has estimated that this figure could increase to 10 million deaths per year by 2050.
“The global antibiotic pharmaceutical market is estimated to reach $44.7 billion in 2020, with an annual growth rate of 5%,” BGU said Monday.
Addressing the role of this method in the fight against antibiotic-resistant infections, Akabayov told the Post that the most successful antibiotics mainly hit three targets in bacteria: the ribosome, cell wall synthesis and the enzyme DNA gyrase.
“Our method will yield inhibitors for targets outside these biochemical pathways, which will be considered as a new class of antibiotics,” he said. “Furthermore, our hybrid method enables the isolation of inhibitors against targeted pathways that cannot be adapted for high-throughput screening and therefore are considered ‘non-drug’ targets.
“Our platform serves as the basis for the development of inhibitors targeting any biochemical pathway,” Akabayov highlighted.
Akabayov also pointed out that with the constant decline in antibiotic agents approved each year by the FDA, there is an urgent need for new antibiotics to address the approaching antibiotic-resistance crisis.
“It is important to point out that our workflow design is applicable not only to antibiotics targeting the ribosome RNA, but also for other RNA targets, such as RNA viruses responsible for diseases such as hepatitis or HIV, as well as for other conditions such as cancer,” he said.
Dr. Galit Mazooz Perlmuter, senior VP of Bio-Pharma Business Development at BGN Technologies, praised Akabayov and his team, emphasizing that this method “provides an efficient, fast and cost-effective route to identifying novel antibiotics that inhibit the ribosome.
“This is extremely important in light of the looming antibiotic-resistance crisis that is predicted by the WHO and other health agencies worldwide,” Perlmuter said. “Following the financial support of the Israel Innovation Authority, [which] sponsored this research, and the promising results to date, we are now seeking an industry partner for further development of this patent pending invention.”
The findings were recently published in Chemical Science, a peer-reviewed scientific journal.
This research was supported by Grant from the United States-Israel Binational Science Foundation (BSF) and the IMTI (TAMAT)/Israel Ministry of Industry–KAMIN Program.View original article