Researchers at Brown and MIT have discovered a way to increase the potency of ADEPs by up to 1,200 times.
A new class of molecules called acyldepsipeptides — ADEPs — may provide a new way to attack bacteria that have developed resistance to antibiotics.
As concerns about bacterial resistance to antibiotics grow, researchers are racing to find new kinds of drugs to replace ones that are no longer effective. One promising new class of molecules called acyldepsipeptides — ADEPs — kills bacteria in a way that no marketed antibacterial drug does — by altering the pathway through which cells rid themselves of harmful proteins.
Now, researchers from Brown University and the Massachusetts Institute of Technology have shown that giving the ADEPs more backbone can dramatically increase their biological potency. By modifying the structure of the ADEPs in ways that make them more rigid, the team prepared new ADEP analogs that are up to 1,200 times more potent than the naturally occurring molecule.
A paper describing the research was released on-line by the Journal of the American Chemical Society.
“The work is significant because we have outlined and validated a strategy for the enhancing the potency of this promising class of antibacterial drug leads,” said Jason Sello, professor of chemistry at Brown and the paper’s senior author. “The molecules that we have synthesized are among the most potent antibacterial agents ever reported in the literature.”
ADEPs kill bacteria by a mechanism by that is distinct from all clinically available anti-bacterial drugs. They work by binding to a protein in bacterial cells that acts as a “cellular garbage disposal,” as Sello describes it. This barrel-shaped protein, called ClpP, breaks down proteins that are misfolded or damaged and could be harmful to the cell. However, when ClpP is bound by an ADEP, it’s no longer so selective about the proteins it degrades In essence, the binding by ADEP causes the garbage disposal to run amok and devour healthy proteins throughout the cell. For bacteria, a runaway ClpP is deadly.
ADEPs have been shown to kill bacteria that cause staph infections, some kinds of pneumonia, tuberculosis, and other types of infection in the lab. The molecules have also been reported to cure bacterial infections in mice and rats.
ADEPs were first discovered as naturally occurring compounds. Certain bacteria produce them for chemical defense. But for the last few years, scientists including Sello’s group have been making synthetic ADEP analogs, in the hope of identifying compounds with potential as new drugs.
One approach the researchers thought might work involves making the ADEP molecule more rigid. Compared to the ClpP molecule to which it binds, the ADEP molecule is a bit “floppy,” Sello said. “We often use the expression ‘lock and key’ to describe how a small molecule binds to a protein. One can imagine that it is easier to fit a rigid key into a lock rather than a floppy key. In the same sense, rigid molecules often bind to their protein targets more tightly.”
Sello and his team synthesized several new ADEP molecules. They swapped out certain amino acids in the naturally occurring molecule with ones they thought might increase the molecule’s rigidity. To find out if the new molecules were indeed more rigid, the team performed experiments that tested the strength of hydrogen bonds within the molecule. Stronger hydrogen bonds would indicate a more rigid molecule.
The researchers placed ADEP molecules in a solution rich in deuterium, a hydrogen atom that has an extra neutron. Over time, the deuterium atoms in the solution will swap places with the hydrogen atoms in the ADEP molecules. The deuterium swap happens more slowly, however, when hydrogen atoms are involved with strong bonds. So if the modified ADEPs exchanged deuterium more slowly, it would be an indication of strong bonds and a more rigid molecule.
The experiments showed that the modified ADEPs exchanged deuterium as much as 380 times more slowly than the natural molecule, a clear indication that the molecules were more rigid.
“It was exciting to see how rather simple modifications to the ADEP structure could affect their rigidity in such a profound manner,” said Daniel Carney, a graduate student in Sello’s group. “More importantly, the results were in line with our ADEP design principle. It is always rewarding when a sophisticated chemical theory can be applied and validated by laboratory experiments.”
To follow up on the prediction that the rigid ADEPs would bind ClpP more tightly, Robert Sauer and Karl Schmitz at MIT measured the capacity of the ADEP analogs and the parent compound to produce the “runaway garbage disposal” phenomenon in solutions containing the ClpP protein. The experiments showed that the modified ADEPs produced the effect at much lower concentrations, indicating a higher binding efficiency. The results implied that the modified molecules were about seven times better than the standard ones at binding to ClpP.
The final step was testing whether the rigid ADEPs were better at killing bacteria in a test tube. Those tests showed that, compared to published reports for standard ADEPs, the modified compounds were much more potent against three different dangerous bacteria — 32 times more potent against S. aureus, 600 times more potent against E. faecalis, and 1,200 times more potent against S. pneumoniae.
Sello was a bit surprised by the dramatic increase in ADEP potency compared to the much more modest improvement in ClpP binding.
The Latest on: Antibiotics
via Google News
The Latest on: Antibiotics
- Antibiotics Market to Witness Massive Growth | Pfizer, Merck, GSK, AstraZenecaon January 15, 2021 at 11:37 pm
Benchmark yourself with the strategic moves and findings recently released by HTF MI Get Free Sample Report + All Related Graphs & Charts @ : Market Overview of Global Antibiotics If you are involved ...
- Antibiotics Market 2021 Share Growing Rapidly with Recent Trends, Development, Revenue, Demand and Forecast to 2026 | Says MarketReportsWorld.comon January 15, 2021 at 5:11 am
Global “Antibiotics Market” report studies the market in-depth and provides an all-encompassing analysis of the key ...
- Scientists make new discovery in the quest for novel antibioticson January 14, 2021 at 9:48 pm
Scientists who highlighted the bug-busting properties of bacteria in Northern Irish soil have made another exciting discovery in the quest to discover new antibiotics.
- Why is Resistance Common in Antibiotics, but Rare in Vaccines?on January 13, 2021 at 9:01 am
Should we be worried about the new vaccines losing efficacy? Luckily, the novel coronavirus has a proof-reading mechanism that reduces the errors it makes when replicating its genome, and means ...
- Global Antibiotics Technologies and Markets, 2018-2019 Data, 2020 Estimates & Forecasts to 2025on January 13, 2021 at 4:00 am
Technologies and Global Markets" report has been added to ResearchAndMarkets.com's offering. The global market ...
- Phage viruses can make superbugs susceptible to antibiotics againon January 12, 2021 at 9:22 pm
Viruses firmly hold the world’s attention at the moment, but we shouldn’t ignore the rising health threat that bacteria pose, too. The crafty critters are fast evolving resistance to antibiotics, ...
- Gene-editing produces tenfold increase in superbug slaying antibioticson January 12, 2021 at 1:22 pm
Scientists have used gene-editing advances to achieve a tenfold increase in the production of super-bug targeting formicamycin antibiotics.
- Why won't antibiotics cure us anymore?on January 12, 2021 at 10:29 am
Current means of fighting bacteria are no longer as good as they used to be because of antibiotic resistance. These days, people are dying from bacterial infections that could have been cured fifty ...
- Why resistance is common in antibiotics, but rare in vaccineson January 11, 2021 at 6:36 am
Antibiotic resistance is a worldwide problem to the extent that there is a grave risk that common infections will soon become untreatable. Meanwhile, vaccines developed nearly a century ago still ...
- Antibiotics not needed after most sinus surgeries: randomized controlled trialon January 6, 2021 at 12:48 am
Antibiotics are not necessary for patients after most routine endoscopic sinus surgeries despite the common practice to prescribe them, according to a team led by researchers at Massachusetts Eye and ...
via Bing News