Nav: Home

Fighting drug resistance with fast, artificial enhancement of natural products

July 08, 2019

Researchers in Japan have identified multiple promising new drug candidates to treat antibiotic-resistant infections, including the superbug MRSA (methicillin-resistant Staphylococcus aureus). The team developed a new technique to enhance the infection-fighting potential of natural chemicals and test them quickly.

In laboratory tests, three of the synthetic molecules that the researchers built are four times more effective at killing bacteria than their natural predecessor, which is itself already an order of magnitude more potent than the current drug used against MRSA, vancomycin.

"Our technique is fast because we can build thousands of new molecules in a single synthesis," said Assistant Professor Hiroaki Itoh from the University of Tokyo Department of Pharmaceutical Sciences.

Researchers first identified the promising new natural antibiotic from a soil sample collected in the subtropical island of Okinawa in southwestern Japan. The antibiotic, called lysocin E, has a unique mechanism of killing bacteria compared to the currently available classes of antibiotics. Even MRSA would be defenseless against it.

Lysocin E has a complex chemical structure that resembles a tambourine: a large ring with 12 short side chains.

The protein building blocks, called amino acids, which form those chains, each contribute to the overall function of the entire molecule. Swapping the naturally occurring amino acids for different ones could enhance the function of the antibiotic.

"We try to find the improvements that natural selection did not make yet," said Itoh.

Researchers focused on four side chains and tested how seven different amino acids might enhance lysocin E's antibacterial activity. All possible combinations of the four side chains and seven amino acids meant that researchers needed to build 2,401 different synthetic versions of modified lysocin E.

Researchers built all 2,401 modified lysocin E simultaneously, one amino acid at a time on top of tiny beads. The beads were divided into seven portions each time researchers reached a part of the molecule where they wanted to vary the amino acid in a side chain. Then all the beads were recombined until researchers reached the location of the next amino acid variation.

"Very few researchers have done this before because many naturally occurring molecules have relatively large and complex structures. This makes them difficult to build synthetically," explained Itoh.

The technique is known as one-bead-one-compound library strategy or split-and-mix synthesis.

Once all 2,401 modified lysocin E were built, researchers tested if they retained the natural version's unique method of killing bacteria. Researchers then removed the molecules from the beads and identified their chemical structures.

Only 22 modified lysocin E were selected for the final round of tests to measure how effective they were at killing six common bacteria in tiny test tubes. Of those, 11 modified lysocin E showed antimicrobial activity better or equal to the original lysocin E.

Researchers will study the three most potent modified lysocin E - defined by the very small amount of drug effective at killing bacteria - to verify their effectiveness at treating infections in nonhuman animal models and to understand the detailed mechanism of how they kill bacteria at such low doses.

"Potentially, our method could be used to find other drug candidates based on promising small protein natural products, including for anti-cancer or anti-virus," said Itoh.

Researchers are confident that their method of synthetically enhancing natural products can increase the speed of early-stage drug discovery, and help maximize the potential of naturally occurring complex molecules.

Besides bacteria, pathogens including HIV (a virus) and malaria (a parasite) are becoming resistant to medications, increasing the potential global health threat of drug resistance. For more information on antibiotic resistance, see the World Health Organization fact sheet: https://www.who.int/news-room/fact-sheets/detail/antibiotic-resistance
-end-
Research Article

Hiroaki Itoh, Kotaro Tokumoto, Takuya Kaji, Atmika Paudel, Suresh Panthee, Hiroshi Hamamoto, Kazuhisa Sekimizu, Masayuki Inoue. Development of a high-throughput strategy for discovery of potent analogues of antibiotic lysocin E. 5 July 2019. Nature Communications. DOI: 10.1038/s41467-019-10754-4. http://dx.doi.org/10.1038/s41467-019-10754-4.

Related Research Article

Hamamoto H, Urai M, Ishii K, Yasukawa J, Paudel A, Murai M, Kaji T, Kuranaga T, Hamase K, Katsu T, Su J, Adachi T, Uchida R, Tomoda H, Yamada M, Souma M, Kurihara H, Inoue M, Sekimizu K. Lysocin E is a new antibiotic that targets menaquinone in the bacterial membrane. Dec 2014. Nature Chemical Biology. DOI: 10.1038/nchembio.1710 https://doi.org/10.1038/nchembio.1710

Related Links

Inoue Laboratory: http://www.f.u-tokyo.ac.jp/~inoue/en/research.html

Graduate School of Pharmaceutical Sciences: http://www.f.u-tokyo.ac.jp/en/

Research contact

Professor Masayuki Inoue
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku Tokyo 113-0033, JAPAN
Tel: (+81)-(0)3-5841-1354
Email: inoue@mol.f.u-tokyo.ac.jp

Press Contact

Ms. Caitlin Devor
Division for Strategic Public Relations, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8654, JAPAN
Tel: +81-3-5841-0876
Email: press-releases.adm@gs.mail.u-tokyo.ac.jp

About the University of Tokyo

The University of Tokyo is Japan's leading university and one of the world's top research universities. The vast research output of some 6,000 researchers is published in the world's top journals across the arts and sciences. Our vibrant student body of around 15,000 undergraduate and 15,000 graduate students includes over 2,000 international students. Find out more at http://www.u-tokyo.ac.jp/en/ or follow us on Twitter at @UTokyo_News_en.

University of Tokyo

Related Bacteria Articles:

Conducting shell for bacteria
Under anaerobic conditions, certain bacteria can produce electricity. This behavior can be exploited in microbial fuel cells, with a special focus on wastewater treatment schemes.
Controlling bacteria's necessary evil
Until now, scientists have only had a murky understanding of how these relationships arise.
Bacteria take a deadly risk to survive
Bacteria need mutations -- changes in their DNA code -- to survive under difficult circumstances.
How bacteria hunt other bacteria
A bacterial species that hunts other bacteria has attracted interest as a potential antibiotic, but exactly how this predator tracks down its prey has not been clear.
Chlamydia: How bacteria take over control
To survive in human cells, chlamydiae have a lot of tricks in store.
More Bacteria News and Bacteria Current Events

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Anthropomorphic
Do animals grieve? Do they have language or consciousness? For a long time, scientists resisted the urge to look for human qualities in animals. This hour, TED speakers explore how that is changing. Guests include biological anthropologist Barbara King, dolphin researcher Denise Herzing, primatologist Frans de Waal, and ecologist Carl Safina.
Now Playing: Science for the People

#534 Bacteria are Coming for Your OJ
What makes breakfast, breakfast? Well, according to every movie and TV show we've ever seen, a big glass of orange juice is basically required. But our morning grapefruit might be in danger. Why? Citrus greening, a bacteria carried by a bug, has infected 90% of the citrus groves in Florida. It's coming for your OJ. We'll talk with University of Maryland plant virologist Anne Simon about ways to stop the citrus killer, and with science writer and journalist Maryn McKenna about why throwing antibiotics at the problem is probably not the solution. Related links: A Review of the Citrus Greening...