Bacteria have lived on earth for billions of years. From the beginning, they had to develop strategies to resist harmful environmental influences and substances. Usually, the defense strategies are active against entire classes of toxic substances. However, the atomic details of the promiscuous, yet specific recognition remained unclear. Using nuclear magnetic resonance spectroscopy the team of Prof. Stephan Grzesiek at the Biozentrum of the University of Basel has now elucidated such a resistance mechanism at the structural level. They demonstrated how a bacterial protein can specifically recognize and inactivate numerous antibiotics belonging to the class of thiopeptides.
Antibiotics with distinct features
Many bacteria produce antibiotics to kill other bacteria in their surroundings and gain a competitive advantage. In parallel, bacteria have developed defense mechanisms against antibiotics during evolution. The protein TipA of the bacterium Streptomyces lividans is such a minimal, promiscuous defense mechanism. TipA binds many different thiopeptide antibiotics and thereby neutralizes them. The binding event also triggers structural changes that stimulate further production of the protein itself. Thereby the harmful thiopeptides are effectively eliminated from the cell.
“It is amazing that these thiopeptides, in spite of their different size and structure, can be recognized specifically by TipA. We have now been able to show how these antibiotics bind to the protein and understand the specific mechanism of recognition”, explains the first author Dr. Judith Habazettl. “All thiopeptide antibiotics contain a previously not recognized, four-ring chemical motif that binds to highly conserved amino acids of TipA.”
Antibiotic action and resistance are linked
A comparison to structures of complexes between ribosomes and thiopeptide antibiotics further revealed that this four-ring thiopeptide motif is also the part of the antibiotic which inhibits the bacterial protein production machinery. Thus the TipA defense mechanism is directed against the same structure that is harmful to the bacterium. “Therefore our study on the resistance mechanism identifies the important parts of the antibiotic and provides us with crucial clues for the development of new antibiotics for medical applications based on thiopeptides”, says Habazettl. As physicians are currently fighting against the increasing resistance of bacteria against conventional antibiotics, hopefully such novel drugs may permit to combat bacterial pathogens in the future.
Judith Habazettl, Martin Allan, Pernille Rose Jensen, Hans-Jürgen Sass, Charles J. Thompson, and Stephan Grzesiek. Structural basis and dynamics of multidrug recognition in a minimal bacterial multidrug resistance system. Proceedings of the National Academy of Sciences, USA; Published online 8 December 2014.
Contact: Communications, Katrin Bühler