Nature Paper Points to New Drug Discovery Direction

May 23, 2001

Contact: Jody Oesterreicher(312) 996-8277; [email protected]

UIC NATURE PAPER POINTS TO NEW DRUG DISCOVERY DIRECTION

Fundamental research at the UIC Center for Pharmaceutical Biotechnology to be published this week in the journal Nature (May 24) could lead to the development of a new class of antibiotics to help combat the growing global health problem of antibiotic resistance.

Roughly two-thirds of all antibiotics kill bacteria by acting on ribosome. They penetrate bacteria and interfere with protein synthesis. Researchers only recently have begun to understand how these antibiotics work.

Alexander Mankin, associate professor of medicinal chemistry in the UIC College of Pharmacy, and his team have found that ribosome can remain functional even after alterations are made to the one nucleotide understood by researchers to be critical for catalytic activity. "The expectation was that if you made mutations at this nucleotide you would kill the ribosome and it no longer would be able to synthesize protein but, in fact, it still could," said Mankin. "We didn't believe it ourselves initially but several independent experiments confirmed our original finding."

This finding brings researchers closer to understanding how ribosome functions and contradicts the commonly held belief among scientists that ribosome functions as a chemical enzyme. It strongly suggests that chemical catalytic activity may not be essential for protein synthesis. Protein synthesis may come about spontaneously when ribosome positions substrates close together. This activity is called peptide bond formation.

Understanding how ribosome functions is likely to enable researchers to understand better how many antibiotics inhibit activity that is critical to bacterial growth.

This finding makes sense from an evolutionary perspective, Mankin says. According to the RNA world theory, life on this planet began as RNA molecules that reproduced without protein. Unlike modern cells in which proteins are catalysts of most chemical reactions, ancient ribosome probably was made of RNA, which is a poor chemical catalyst but efficient at binding substrates. Researchers do not yet understand the transition from RNA growth to modern cell growth, in which the reaction is catalyzed by protein. Though proteins have assumed many RNA functions, it still is RNA that promotes peptide bond formation.

The UIC team's finding suggests that drugs that interfere with binding of ribosomal substrates may block bacterial protein synthesis and, hence, be most effective against antibiotic-resistant bacteria.

The next step for Mankin's UIC laboratory is to determine whether ribosome can function without proteins. The UIC researchers are most interested in ribosomal RNA, in part because the main target of antibiotics that act on ribosome is not protein, but RNA.

The UIC laboratory is working to understand how ribosome works in general and how antibiotics that affect ribosome work.

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