UIC Scientists Discover How Some Bacteria Survive Antibiotics
[Writer] This is Research News from U-I-C, the University of Illinois at Chicago.
Today, Alexander Mankin, Professor and Associate Director of the University of Illinois at Chicago’s Center for Pharmaceutical Biotechnology talks about how some bacteria can survive antibiotic treatment by turning on resistance mechanisms when exposed to the drugs.
Here’s Professor Mankin:
[Mankin] People sometimes think that the basic science is a way for crazy scientists to satisfy their curiosity on the expense of the taxpayers. The reality is basic science provides underpinnings for all the major discoveries in medicine and in the pharmaceutical industry—the discoveries which help us to understand the nature of many diseases and discoveries which help to develop new drugs, new treatments for human illnesses.
I think that our drug is an example of how basic science can potentially contribute to the medicine and the development of new drugs. In our studies, we were interested in the very exciting phenomenon, a phenomenon that had been described for the first time about thirty years ago but whose mechanisms were not understood until recently. The phenomenon is called Inducible Antibiotic Resistance. Everyone knows that one of the big problems of modern medicine is that pathogenic bacteria can become resistant to antibiotics. The interesting thing about antibiotic resistance is that bacteria have to pay a high price for being resistant. They need to make a special enzyme which will inactivate antibiotics and will help bacteria survive the antibiotic assault. There are especially smart bacteria that have developed a system of early warning. The bacteria don’t normally make the resistance enzyme until antibiotic is present. And only when we start treating patients the drug appears in the blood stream. Those smart bacteria can sense the presence of this antibiotic and then they start making the resistance enzyme.
So what we tried to understand in our group is how the system of early warning works for these bacteria. The antibiotic we worked with is called erythromycin, which belongs to a member of macrolide antibiotics—very useful clinical drugs which includes such modern compounds as azithromycin, clarithromycin and many others. All these drugs act up on the ribosome, the big macromolecular complex which makes all the proteins in the cell. All the proteins are made inside the ribosome and on the way out they pass through a special tunnel, a hole in the body of the ribosome. Usually, until recently, scientists thought that the ribosome does not interact with the proteins that it’s made. Now the tunnel is like a Teflon tube and all the proteins slide very easily through this tunnel. The interesting thing is that erythromycin and similar drugs bind inside the tunnel. In order to activate the expression of resistance enzymes, this smart bacterium has developed a very delicate system. A system includes two ribosomes which make two very different products. One ribosome is all the time making a very, very small peptide. This peptide is so small that it costs the cell almost nothing to make it. Therefore, cells make it all the time, respective of whether the antibiotic is present or not. Only when antibiotics appears in the medium, in the patient’s body, and the antibiotic binds in the ribosomal tunnel, then the ribosome stops making this peptide, and it stops making this peptide by sensing this presence of the drug. When it stops making this peptide, it sends a signal to another ribosome to start making the resistant enzyme so the cell can become resistant.
So what we’re trying to understand in our work is how the ribosome senses the presence of antibiotics, how does it stop making the protein and how the signal is generated, which is eventually sent to the other ribosome responsible for making the resistance enzyme. The researchers in my laboratory, Dr. Nora Vazquez Laslop, and an undergraduate student interestingly enough, Celine Thum, they did a very nice biochemical and genetic work to sort out how the ribosome responds to the presence of the drug. They did mutations in the ribosome, they changed the nature the peptide and they tried a collection of different antibiotics to see what combination of the components allow ribosomes to stall and to send a signal to the other ribosome.
We think that we have understood some aspects of how the system works. We don’t know all the details and we are trying now to work out all the details of operation of this mechanism, but the knowledge that we have gained in this reasonably basic research can already help to direct the development of new antibiotics, the antibiotics which will bind to the ribosome but will not induce resistance of the antibiotic enzyme. Those antibiotics will be better drugs in the hospital and they will be able to kill the bacteria which carry the inducible resistance mechanism.
[Writer] Alexander Mankin is Professor and Associate Director of the Center for Biopharmaceutical Technology.
For more information about this research, go to www.today.uic.edu, click on news releases and look for the release dated April 30, 2008.
This has been research news from UIC – the University of Illinois at Chicago.
