Binding to FabF
Week of May 20, 2006; Vol. 169, No. 20 , p. 307
Bug Zapper: Novel drug kills resistant bacteria
Nathan Seppa
A newly recognized compound can wipe out some of the most troublesome antibiotic-resistant bacteria, laboratory tests show. The drug works by sabotaging a microbe's production of fatty acids.
Scientists at Merck Research Laboratories in Rahway, N.J., discovered the compound, which they call platensimycin.
The findings are preliminary but impressive, says Eric D. Brown, a microbiologist at McMaster University in Hamilton, Ontario. "This is a really promising story in a field that has had quite a bit of disappointment," he says.
Roughly 90,000 people in the United States acquire fatal infections in hospitals every year, according to data from the Centers for Disease Control and Prevention in Atlanta. Nearly three-fourths of those deaths can be traced to antibiotic-resistant microbes.
Most antibiotics were developed at least 50 years ago (SN: 5/28/05, p. 347: Available to subscribers at http://www.sciencenews.org/articles/20050528/bob9.asp). Those made more recently are almost all variants of the early drugs and work by attacking the bacterial cell wall or DNA- or protein-synthesis machinery.
Merck chemist Sheo B. Singh and his colleagues screened roughly 250,000 natural compounds in search of potent antibacterials. This approach makes sense, Brown says, because organisms in nature "are constantly in warfare with each other." He notes that natural compounds work well as drugs because they target specific weaknesses in rival organisms.
The search led to platensimycin, a small molecule made by the bacterium Streptomyces platensis. That bug normally lives in soil in South Africa.
In the May 18 Nature, the researchers report that platensimycin promptly kills lab-dish colonies of staphylococcus and enterococcus bacteria that resist drugs such as vancomycin and methicillin. When the researchers continuously infused mice with the drug in a first test, it killed Staphylococcus aureus that wasn't drug resistant.
Platensimycin is structurally different from other antibiotics. Unlike most of those drugs, it binds to and neutralizes an enzyme called FabF, which bacteria use to make fatty acids. Platensimycin "preexisted in nature to get this job done," Brown says. "This was pretty good detective work at Merck."
Fatty acids are essential for building and maintaining the membrane that lines the bacterial cell wall. FabF is different from the corresponding enzyme in mammals, suggesting that platensimycin won't inhibit fatty acid synthesis in people, says Charles O. Rock, a biochemist at St. Jude Children's Research Hospital in Memphis, Tenn.
This is the fourth natural compound—and by far the most potent—found to target FabF, Rock notes. "Nature is telling us again and again that if you want to go after bacteria, go after this enzyme," he says.
"If we look long enough and hard enough, we'll find these [fatty acid] inhibitors," says Steven J. Projan, a microbiologist at Wyeth Pharmaceuticals in Cambridge, Mass. But he cautions that the Merck team found it necessary to continuously infuse the drug in the mouse tests. That suggests that platensimycin might be metabolized too quickly in people to make a good drug candidate. Still, the study shows that derailing fatty acid synthesis can kill bacteria, Projan says.
The new finding "just goes to show you how marvelously clever nature is at blocking enzyme activity," says Brown.
Despite the heady results, the Merck scientists had no comment on whether the company would pursue further development of platensimycin.
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One of the few advantages of getting older is having perspective on these kinds of subjects.
In the 1970's we were screamed at by 'the sky is falling' crowd that we were about to run out of effective antibiotics, as the germs had just about outfoxed us again, and we all were going to die from something that was resisitant to penicillin.
As you know, that never happened.
Nature has a way of balancing these things out. With this new antibotic mentioned in the article we are going to have the upper hand for awhile, maybe even for decades. Nature will then find a way to fill the void, and we will be off for another round to fight.
"We do need new antibiotics"
Yes, we need something more powerful for the stupid people to demand from their doctor when they have a cold.
If it's found in nature, it's not patentable, so no drug company will market it. They need to find a variation they can patent, so no one else can sell it.
Binding to FabF
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