'Smart Antibiotics' 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."

In the Nature paper, the team reports the discovery of how the mechanism works to target mutations, its wide distribution in nature, and features of the mechanism that relate to applications for using it. Miller's team is continuing to study the mechanism, to learn more about its biochemical properties, and to determine whether higher forms of life have similar cassettes. "We're now searching the genomes of higher life forms," Miller said.

Miller believes his research team will be able to exploit the new knowledge to generate proteins in the laboratory that will bind to almost any molecule of interest. "We think we can make proteins that bind to peptides, and make peptides that bind to larger proteins," he said.

As is often the case in science, the project was initially undertaken for an unrelated reason. Minghsun Liu, a former UCLA M.D.-Ph.D. student in Miller's laboratory, was looking for bacterial viruses to study genetics when he found a remarkable property in a particular virus. Miller's team decided to study the phenomenon. Liu is now an infectious disease fellow at Stanford University.

"This was serendipitous, nothing we ever looked for," Miller said. "Serendipity is emblematic of many discoveries in science."

The research team includes Sergei Doulatov, former UCLA undergraduate and former research associate in Miller's laboratory; Steven Zimmerly, professor of biochemistry at the University of Calgary; graduate student Lixin Dai at the University of Calgary; Rajendar Deora, a former postdoctoral scholar in Miller's laboratory; Neeraj Mandhana, an undergraduate student in Miller's laboratory; and Robert Simons, UCLA associate professor of microbiology, immunology and molecular genetics. The research was funded by the National Institutes of Health.

(C) 2004 UCLA

Doulatov S, Hodes A, Dai L, Mandhana N, Liu M, Deora R, Simons RW, Zimmerly S, Miller JF.
Tropism switching in Bordetella bacteriophage defines a family of diversity-generating retroelements.
Nature. 2004 Sep 23;431(7007):476-81.

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