For 50 years scientists have been unsure how the bacteria
that gives humans cholera manages to resist one of our basic innate immune
responses. That mystery has now been solved, thanks to research from biologists
at The University of Texas at Austin.
The answers may help clear the way for a new class of
antibiotics that don’t directly shut down pathogenic bacteria such as V. cholerae, but instead disable their
defenses so that our own immune systems can do the killing.
Every year cholera afflicts millions of people and kills
hundreds of thousands, predominantly in the developing world. The infection
causes profuse diarrhea and vomiting. Death comes from severe dehydration.
“If you understand the mechanism, the bacterial target,
you’re more likely to be able to design an effective antibiotic,” says Stephen
Trent, associate professor of molecular genetics and microbiology and lead
researcher on the study.
The bacterium’s defense, which was unmasked in the Proceedings of the National Academy of Sciences,
involves attaching one or two small amino acids to the large molecules, known
as endotoxins, that cover about 75% of the bacterium’s outer surface.
“It’s like it’s hardening its armor so that our defenses
can’t get through,” says Trent.
Trent says these tiny
amino acids simply change the electrical charge on that outer surface of the
bacteria. It goes from negative to neutral.
That’s important because the molecules we rely on to fight
off such bacteria, which are called cationic antimicrobial peptides (CAMPs),
are positively charged. They can bind to the negatively charged surface of
bacteria, and when they do so, they insert themselves into the bacterial
membrane and form a pore. Water then flows through the pore into the bacterium
and pops it open from the inside, killing the harmful bacteria.
It’s an effective defense, which is why these CAMPs are
ubiquitous in nature (as well as one of the main ingredients in
over-the-counter antibacterial ointments such as Neosporin).
However, when the positively charged CAMPs come up against
the neutral V. cholerae
bacteria, they can’t bind. They bounce away, and we’re left vulnerable.
V. cholerae can then invade our intestines and turn
them into a kind of factory for producing more cholera, in the process
rendering us incapable of holding onto fluids or extracting sufficient
nutrients from what we eat and drink.
“It pretty much takes over your normal flora,” says Trent.
Trent says that
scientists have known for some time that the strain of V. cholerae responsible for the current
pandemic in Haiti
and elsewhere is resistant to these CAMPs. It’s that resistance that is likely
responsible, in part, for why the current strain displaced the strain that was
responsible for previous pandemics.
“It’s orders of magnitude more resistant,” says Trent.
Now that Trent and his colleagues understand the mechanism
behind this resistance, they hope to use that knowledge to help develop
antibiotics that can disable the defense, perhaps by preventing the cholera
bacteria from hardening their armor. If that happened, our CAMPs could do the
rest of the work.
Trent says the benefits
of such an antibiotic would be considerable. It might be effective against not
just cholera but a range of dangerous bacteria that use similar defenses. And
because it disarms but doesn’t kill the bacteria outright, as traditional antibiotics
do, it might take longer for the bacteria to mutate and evolve resistance in
response to it.
“If we can go directly at these amino acids that it uses to
protect against us, and then allow our own innate immune system to kill the
bug, there could be less selection pressure,” he says.
Trent’s
laboratory is now screening for compounds that would do precisely that.
Source: University of Texas at Austin
Filed Under: Drug Discovery
