The bouncer at the binding site
Many bacterial infections can be cured by treatment with antibiotics, but overuse and inappropriate dosage have led to the rapid emergence of resistances, rendering several of our most valuable anti-bacterial agents ineffective. Antibiotics with novel modes of action are therefore urgently needed, and, to develop new drugs, one needs to understand how current agents act and how resistances evolve. Daniel Wilson’s group at LMU’s Gene Center is pursuing this goal, and their latest study overturns a widely accepted model for one mechanism of resistance to tetracycline.
Tetracyclines are among the broad-spectrum antibiotics most frequently prescribed. Like many others, they bind to bacterial ribosomes and prevent the synthesis of the proteins that essential for cell growth and propagation. “Resistance to tetracyclines can arise in several different ways,” says Wilson, who is also affiliated with the Center for Integrated Protein Science Munich (CiPSM), an Excellence Cluster at LMU. In most cases, the antibiotic is either pumped out of the cell by an efflux protein or dislodged from its binding site by a ribosome protection protein (RPP).
TetM evicts ribosome-bound tetracycline
It has generally been assumed that RPPs function indirectly by altering the overall structure of the ribosome in such a way that the antibiotic no longer fits comfortably into its docking site. Wilson and his colleagues have now used cryo-electron microscopy to elucidate the three-dimensional structure of the complex formed between the ribosome and the RPP TetM that confers resistance to tetracycline. “We were able to show that TetM itself interacts directly with the tetracycline binding site to actively displace the antibiotic from the ribosome,” he says.
As Wilson explains, the results of the study have implications for efforts to develop new antibiotic compounds. “Our new insights into the structural basis for tetracycline resistance could make a significant contribution to guiding the development of a new generation of tetracycline analogs,” he says. (PNAS, 14. September 2012) göd
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