Doctors may soon have a new weapon in the long-running war between antibiotics and bacteria. It’s a Swiss Army knife of a drug that’s tens of thousands of times more effective in lab tests against dangerous antibiotic-resistant bacteria.
Starting with the discovery of penicillin in 1928, scientists and doctors have been finding and making molecules that weaken or kill bacteria in a range of different ways to help humans survive infections. And as soon as humans started employing these antibiotics, bacteria began evolving to beat those attacks.
That has started to become a huge problem. So-called superbugs like methicillin-resistant Staphylococcus aureus (MRSA) can ward off some of our most potent antibiotics, making infections by these bacteria extremely hard to treat. Not only that, but their existence poses a strategic challenge as well, forcing doctors to think hard about when and where they use certain antibiotics, lest bacteria develop resistance to them and render them less effective.
Vancomycin is one antibiotic that has stayed effective even as others have been brought down by resistant bacteria. That’s because of the way vancomycin works: by latching onto one of the building blocks bacteria use to build their cell walls, like the microscopic equivalent of a bully stealing your shovel in the sandbox and not giving it back. (In this analogy, we’re on the bully’s side.)
By interfering with such a critical cellular process in such a fundamental way, vancomycin makes it hard for bacteria to develop a simple mutation to defeat the antibiotic. That makes vancomycin one of our last lines of defense for treating infections like MRSA that others can’t. It’s why the World Health Organization (WHO) added the drug to its list of essential medicines.
Naturally, some bacteria have found ways to fight vancomycin, the most common being to substitute a different cell wall building block that the antibiotic can’t latch onto. Taking vancomycin out of doctors’ quivers would be a big blow. Which is why the WHO also lists vancomycin-resistant bacteria at number four and five on its list of the most threatening antibiotic-resistant microbes.
So. To try to make sure vancomycin can beat those resistant bacteria, and stay effective for the next few decades—a reasonable lifetime for an antibiotic—chemists Dale Boger, Nicholas Isley and Akinori Okano at the Scripps Research Institute in California opened up the hood to make a few adjustments to the molecule.
After swapping out one part and bolting on a couple others, the group’s souped-up vancomycin was about 25,000 times more potent against resistant bacteria, and it had better endurance. They describe their work in the Proceedings of the National Academy of Sciences.
The major change was to the region of the molecule that grabs those cell wall building blocks, which are called D-alanyl-D-alanine. Resistant bacteria have learned to substitute the very similar D-alanyl-D-lactate, which your standard vancomycin can’t bind to very well, limiting its effectiveness. The researchers changed an oxygen atom for two atoms of hydrogen, making a new version of vancomycin that could hang onto either building block.
Then, because why quit while you’re ahead, they added two new features to the molecule. One weakens bacteria cell walls. The other further disrupts the cell wall building process. Those each made the modified vancomycin 200- and 100-times more effective, respectively.
And not only is their improved vancomycin better at killing bacteria, it appears to be hold up against their attempts to evolve defenses. In the lab, the researchers tested their new molecule against successive generations of bacteria without seeing any appreciable gain in their resistance.
The researchers say their molecule’s multipronged attack is the key to its effectiveness, and its resistance to resistance. “Organisms just can't simultaneously work to find a way around three independent mechanisms of action.
Even if they found a solution to one of those, the organisms would still be killed by the other two,” Boger told the BBC. Because if they can't survive, they won't pass on mutations to future generations.
Like I've said before, keep in mind that a promising molecule is still a long way from doctors having a new drug to rely on. Successful laboratory tests don’t necessarily mean it will work in the real world, or be safe for humans to use, although this group’s work suggests both those things should be true. And it’s a hopeful sign that chemists will be able to keep us at least a step ahead of bacteria in our ongoing clash.
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That has started to become a huge problem. So-called superbugs like methicillin-resistant Staphylococcus aureus (MRSA) can ward off some of our most potent antibiotics, making infections by these bacteria extremely hard to treat. Not only that, but their existence poses a strategic challenge as well, forcing doctors to think hard about when and where they use certain antibiotics, lest bacteria develop resistance to them and render them less effective.
By interfering with such a critical cellular process in such a fundamental way, vancomycin makes it hard for bacteria to develop a simple mutation to defeat the antibiotic. That makes vancomycin one of our last lines of defense for treating infections like MRSA that others can’t. It’s why the World Health Organization (WHO) added the drug to its list of essential medicines.
Naturally, some bacteria have found ways to fight vancomycin, the most common being to substitute a different cell wall building block that the antibiotic can’t latch onto. Taking vancomycin out of doctors’ quivers would be a big blow. Which is why the WHO also lists vancomycin-resistant bacteria at number four and five on its list of the most threatening antibiotic-resistant microbes.
So. To try to make sure vancomycin can beat those resistant bacteria, and stay effective for the next few decades—a reasonable lifetime for an antibiotic—chemists Dale Boger, Nicholas Isley and Akinori Okano at the Scripps Research Institute in California opened up the hood to make a few adjustments to the molecule.
After swapping out one part and bolting on a couple others, the group’s souped-up vancomycin was about 25,000 times more potent against resistant bacteria, and it had better endurance. They describe their work in the Proceedings of the National Academy of Sciences.
The major change was to the region of the molecule that grabs those cell wall building blocks, which are called D-alanyl-D-alanine. Resistant bacteria have learned to substitute the very similar D-alanyl-D-lactate, which your standard vancomycin can’t bind to very well, limiting its effectiveness. The researchers changed an oxygen atom for two atoms of hydrogen, making a new version of vancomycin that could hang onto either building block.
Then, because why quit while you’re ahead, they added two new features to the molecule. One weakens bacteria cell walls. The other further disrupts the cell wall building process. Those each made the modified vancomycin 200- and 100-times more effective, respectively.
And not only is their improved vancomycin better at killing bacteria, it appears to be hold up against their attempts to evolve defenses. In the lab, the researchers tested their new molecule against successive generations of bacteria without seeing any appreciable gain in their resistance.
The researchers say their molecule’s multipronged attack is the key to its effectiveness, and its resistance to resistance. “Organisms just can't simultaneously work to find a way around three independent mechanisms of action.
Even if they found a solution to one of those, the organisms would still be killed by the other two,” Boger told the BBC. Because if they can't survive, they won't pass on mutations to future generations.
Like I've said before, keep in mind that a promising molecule is still a long way from doctors having a new drug to rely on. Successful laboratory tests don’t necessarily mean it will work in the real world, or be safe for humans to use, although this group’s work suggests both those things should be true. And it’s a hopeful sign that chemists will be able to keep us at least a step ahead of bacteria in our ongoing clash.
View at the original source
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