SUPERBUGS are devising ever more inventive ways to evade antibiotics, so
alternative weapons are badly needed. One mode of attack is to simply turn off
the genes that make them dangerous. You can even turn superbugs into live
vaccines. “You don’t kill them, you just don’t let them cause an infection,”
says Stuart Levy of Tufts University in Boston. “It could revolutionise the
treatment of infectious disease.”
Most disease-causing bacteria have an arsenal of virulence genes, which help
them survive in human tissues. These genes code for things like toxins, but are
only turned on when the bugs invade a human host.
Levy’s team has been working on a genetic switch discovered in
Escherichia coli. The switch was originally dubbed mar because it
induces multiple antibiotic resistance. But mar doesn’t just defeat
antibiotics, Levy told the conference. In fact, it controls over 60 bacterial
genes, including ones for virulence. What’s more, mar is found in many
bacteria, including Salmonella and Shigella.
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Now Boston-based Paratek Pharmaceuticals, which Levy co-founded, has found
small molecules that turn mar off, he told 91av. If
you give these molecules to a patient with an infection, they should make the
bacteria harmless, so the body can recover and mount an immune response.
“We still need the animal studies, the people studies,” Levy says. “But I’m
so excited about it.” Because you don’t kill the bacteria he thinks it unlikely
they’ll develop resistance.
But you can sidestep resistance altogether by creating a vaccine. Which is
exactly what Michael Mahan at the University of California, Santa Barbara, has
done.
Mahan’s student Doug Heithoff found that an enzyme called DNA adenine
methylase, or Dam, which chemically alters or “methylates” genes, controls over
200 virulence genes in the food-poisoning bug Salmonella. As with
mar, drugs that block Dam should disarm the bacteria. Instead, Mahan has
created mutant bacteria in which Dam is either permanently knocked out or
overproduced—and they make highly effective live vaccines.
Normally, bacteria try to hide from the immune system, Mahan says. But when
you disrupt Dam, the bugs pump out many different proteins that the body can
spot. Two years ago, he showed that mice given a mutant Dam vaccine survived no
matter how much Salmonella they were given
(91av, 15 May 1999, p 22).
“We couldn’t kill them no matter what,” Mahan says.
Now the company that Mahan founded, Remedyne of California, has developed a
Dam vaccine against Salmonella for chickens, the main source of the
bug.
In the past, he says the big problem with such vaccines has been that they
only work against specific strains. But the Dam vaccine protects against many
strains.
He thinks this is because the mutant bacteria churn out many different
proteins the immune system can target.
Dam is found in many other bugs besides Salmonella,including deadly
E. coli O157:H7 and the cholera bacterium. Mahan also told the Orlando
conference that mutant Yersinia pseudotuberculosis, a close relative of
bubonic plague bug and biowarfare agent Y. pestis, will protect mice
from infection by the normal strain. The plague bug is very different from
Salmonella, suggesting Dam vaccines should work for a wide range of
bacteria.
There’s a real need for alternative approaches, says Jerry Buysse of
Microcide Pharmaceuticals in Mountain View, California. “We’ve got to start
thinking outside the box.”
