“Resurrected ancient protein is a potent antibiotic”
September 24, 2011 1 Comment
As you may know, there’s an alarming trend of pathogens evolving resistance to multiple drugs, and our arsenal of weapons with which to fight them is shrinking. When you kill 99% of a particular germ with a drug, the 1% that randomly had a resistance to it suddenly has lots of real estate and grows out of control – and obviously can’t be killed the same way. The more we use antimicrobial drugs, the worse this problem gets.
So researchers are looking for more solutions, drugs that current microbes have never seen before, and this brings us to this piece of news via the New Scientist. In short, researchers found some proteins in the wallaby immune system that looked like 1) they could kill a variety of drug-resistant microbes and 2) they wouldn’t be toxic to humans. They found a few very similar genes for these proteins and used the differences between them to predict the sequence of their genetic ancestor – the common gene from which they all evolved – which they predicted would have a broad range of activity. And they synthesized the predicted protein – and it works.
IF MODERN medicine cannot provide an answer to multidrug-resistant microbes, perhaps ancient animals can. Biologists have resurrected a mammalian antimicrobial compound that was last seen on Earth 59 million years ago when mammals were recovering from the Cretaceous-Tertiary extinction that wiped out the dinosaurs. Even now it is potent enough to destroy some of our most troublesome pathogens…
Conventional antibiotics target precise flaws in a pathogen’s armour, such as a particular enzyme. This is similar to how the adaptive immune system found in vertebrates works: it learns how to fight a new pathogen and then remembers the lesson for future battles. The trouble is that the pathogens patch their armour, requiring the immune system – and drug companies – to identify new weaknesses.
Cocks says this evolutionary arms race can be side-stepped by falling back on the cruder innate immune system that is found in all plants and animals – and which has largely been ignored in our fight with multidrug-resistant pathogens.
The molecules of the innate immune system use simple chemistry to target the lipids in cell membranes. They can either disrupt and weaken bacterial membranes, or subtly alter the properties of the host’s healthy cells so that pathogens can no longer attack them.
To be clear, the innate immune system is a part of the immune system complementary to the adaptive immune system; the former non-specifically attacks invading pathogens, while the latter is activated by the former and develops antibodies to particular pathogens, granting better protection for future infections.
But there’s a problem: animals with the strongest innate immune systems tend to be so distantly related to humans that molecules taken from them can have toxic effects in humans. Cocks’s solution is to study the mammals with the best innate immune systems, the molecules of which are more likely to be compatible with humans. His work has taken him inside the wallaby’s pouch.
… Bacteria closely related to the superbugs affecting humans in hospitals have been found in the wallaby pouch. But the baby wallabies are so underdeveloped that they lack an adaptive immune system to fight them; their survival depends on their innate immune system.
Cocks’s team scoured the wallaby genome and found genes that code for 14 cathelicidin peptides, a component of the innate immune system. Lab tests revealed that many of the peptides could kill a range of multidrug-resistant pathogens – without damaging human cells.
The team noticed that genes in five of the cathelicidins were remarkably similar and probably evolved from a single ancestor. “We thought that the ancestral form would have a special broad-range activity,” says Cocks.
Using the changes within the five peptides, Cocks and his collaborators at the University of Sydney, Australia, worked backwards to predict the genetic sequence that codes for the original peptide. His team then used it to produce a synthetic version of the peptide, effectively resurrecting it.
“The amazing thing was that it worked well against a broad range of pathogens,” he says. Lab tests showed it destroyed six of seven multidrug-resistant bacteria, and was 10 to 30 times more potent than modern antibiotics such as tetracycline.
I wonder if other groups have synthesized predicted ancient proteins? Seems like a pretty interesting process. My one problem with this article is the terminology of “resurrecting” a protein, as if a protein were considered alive on its own – seems like it’s just bound to confuse people.