New UCLA research may lead to an effective alternative to antibiotic drugs for treating bacterial diseases.
UCLA microbiologists report the discovery of a new class of genetic elements, similar to retroviruses, that operate in bacteria, allowing them to diversify their proteins to bind to a large variety of receptors. The team discovered this fundamental mechanism in the most abundant life-forms on Earth: bacteriophages, the viruses that infect bacteria.
"A problem with antibiotics is that bacteria can mutate and become resistant to a particular antibiotic, while the antibiotic is static and cannot change," said Jeffery F. Miller, professor and chair of microbiology, immunology and molecular genetics at UCLA, who holds UCLA's M. Philip Davis Chair in Microbiology and Immunology, and who led the research team. "Bacteriophages ("phages") are nature's anti-microbials, and they are amazingly dynamic. If the bacterium mutates in an effort to evade, the bacteriophage can change its specificity using the mechanism we discovered, to kill the newly resistant bacterium."
The use of bacteriophage to treat infections is not in itself a new idea. "Phage therapy has been practiced for nearly a hundred years in parts of the world, and even in the United States in the first half of the 20th century. But now, we think we can engineer bacteriophages to function as 'dynamic' anti-microbial agents. This could provide us with a renewable resource of smart antibiotics for treating bacterial diseases," said Miller, a member of both UCLA's David Geffen School of Medicine and the UCLA College.
"It's a bit ironic that viruses can be used to cure bacterial diseases," said Asher Hodes, a UCLA graduate student in microbiology, immunology and molecular genetics, and a member of the research team. "This approach can be effective, especially for diseases where traditional antibiotics do not work well. There is the potential for treating bacterial infections using genetically engineered phages that will efficiently overcome bacterial resistance."
Bacteriophages evolve rapidly and are a "treasure-trove of fascinating biological mechanisms," Miller said. His research team studied a bacteriophage that was able to change to recognize different receptor molecules on the surface of bacteria. The phage genome contains a series of genes, identified by Miller's team, that enable this fast-change routine. The researchers discovered that the phage's genome contains a "little genetic 'cassette' that functions to diversify the part of the virus that binds to the bacterial cell. That cassette allows the phage to rapidly evolve new variants that can recognize bacteria that may have become resistant to the previous phage," Miller said.
The microbiologists initially discovered the mechanism in a bacterial virus that infects Bordetella bronchiseptica, the "evolutionary parent" of the bacterium that causes whooping cough.
How widespread is this mechanism? Through bioinformatics and analysis of DNA sequences, Miller's team has found evidence for many other cases where either bacteriophage or bacteria use the same strategy for targeting mutations and speeding up evolution. "We're eager to determine how widespread it is; the more we look, the more we find it," Miller said. "And the more we study it, the more ingenious the mechanism appears to us."