BioWorld International Correspondent
LONDON - A pair of bacterial proteins that might play a role in repairing holes in the bacterial cell wall could provide interesting new targets for antibiotics or vaccines to protect against infectious diseases.
Curiously, genome biologists in Germany studying the proteins predict that one of them might have evolved first in animals, but then transferred to bacteria through evolution.
Aidan Budd, a Ph.D. student at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, told BioWorld International: "We think that these proteins are involved in defending the bacterial cell against attack by the host's enzymes. They might, for example, inactivate host proteases that attempt to weaken the bacterial cell wall."
Toby Gibson, team leader at EMBL, said: "This study gives us insight into how infectious bacteria function - microbes that cause diseases such as pneumonia, whooping cough and plague are using our own gene against us. With this new information, we could potentially produce antibodies to give our immune systems a way to identify the bacteria and block the activity of these weapons."
A paper on their work - titled "Bacterial a2-macroglobulins: colonization factors acquired by horizontal gene transfer from the metazoan genome?" - appears in the May 26, 2004, issue of Genome Biology.
The investigation by Gibson, Budd and their colleagues was triggered when Stephanie Blandin and Elena Levashina, both at EMBL at the time, wanted to use computational methods to find out more about a gene they had identified in mosquitoes. The gene encoded a blood protein called thioester-binding protein, a member of the a2-macroglobulin (a2-M) family, which they knew helped to defend the mosquito against attacking parasites. Such proteins are important for blood-sucking insects such as mosquitoes, because through their food source they encounter many pathogens.
Budd said: "During a search of databases for genes similar to a2-M, we were very surprised to discover a bacterial a2-M gene. There are no previous reports of such a finding."
Further investigations showed that the a2-M gene was commonly associated in bacterial genomes with a second gene, called pbp1C. The latter turned out to encode a protein that has a role in synthesizing bacterial cell walls. It is a member of a family of genes that encode proteins used as targets for penicillin, which look similar to their own substrates. But, unlike some other members of that family, when pbp1C is knocked out in bacteria, it does not appear to affect their ability to grow.
Budd said: "It appears that pbp1C synthesizes cell walls of bacteria in a different way [from] other similar enzymes. It works very fast, which would allow it to quickly repair holes in cell walls caused by host defenses."
The two genes are found only in Gram-negative bacteria. The team suggested that they might be located in the space between the two bacterial membranes and only become active if the outer membrane is breached.
That characteristic could make those two genes targets for selective antibiotics. Budd said: "It would be an advantage with many antibiotics to be able to avoid killing off all the friendly bacteria that live in our bodies, too. Pbp1C and a2-M might offer a way of attacking only those bacteria that have already been attacked by host cells, which are therefore most likely to be invaders and pathogens."
The group hopes that other scientists will follow their lead.
"Researchers will need to check that these proteins are indeed located in the periplasm of bacterial cell walls, as we predict," Budd said. "We have also hypothesized that a2-M traps host proteases, and we need to know if this is true. It will also be important to find out if bacteria that have had one or both of these genes knocked out are more sensitive to lysozyme - a protein that humans produce to lyse the cell walls of bacteria."
Finally, Budd said, he hopes that some teams will investigate a2-M and pbp1C as targets for vaccines against infectious diseases or for antibiotics.