A joint team of researchers from Brown and the Massachusetts Institute of Technology have successfully killed bacteria resistant to typical antibiotics by increasing the potency of a class of molecules called acyldepsipeptides, or ADEPs. Their study was published Jan. 14 in the Journal of the American Chemical Society.
ADEPs are peculiar, said Jason Sello, lead author of the study and associate professor of chemistry. “They have a different mechanism of action.”
The ADEP molecules target ClpP, a “garbage disposal protein” whose job in the bacteria is to decompose other proteins no longer necessary in the cell, said Daniel Carney GS, a co-author of the study.
“It’s a very important process in all living organisms to be able to recycle proteins into the building blocks proteins are made from,” Carney said. Cells want ClpP to degrade specific proteins at specific times, he added.
The ADEP molecule turns ClpP into a “garbage disposal run amok” that will degrade all kinds of proteins essential to the cell, Carney said. Once the ADEP causes the ClpP to lose control, the bacteria dies.
“There are just a handful of targets we know to exploit,” said Andrew Phillips, a professor of chemistry at Yale University not involved the study. “ClpP is what you would call an emerging opportunity.”
“There are no drugs on the market that target ClpP,” Sello said.
More than two million people are infected by drug-resistant bacteria, Sello said, referring to a 2013 Centers for Disease Control threat report. These bacteria kill 23,000 people a year, he added.
Origins of and synthesizing ADEPs
The original ADEPs were antibacterial compounds produced by living organisms, Carney said. “But it turned out that the natural products, although they were interesting antibacterial compounds, were not good drug candidates,” he added. “While they killed bacteria on a petri dish, if you tried to actually cure an infection in a mouse, the natural products didn’t work.”
In the mid-2000s, a company called Bayer Healthcare began to manipulate ADEPs with an eye toward drug development, Carney said, adding that they tried to rigidify the ADEP compound to make it bind to a target protein.
“In order for a small molecule to bind to a protein, it needs to first be the same shape, just like a key needs to be the right shape to fit into the lock,” Carney said. Similar to the way keys need to be rigid to fit into a key hole, molecules need to be rigid to bind tightly to a target, he added.
In their study, Carney and his colleagues synthesized ADEP molecules of different levels of rigidity, including some less rigid than the Bayer compound and some much more rigid, he said.
“In the main text there’s not really a lot of discussion about the chemical synthesis and where these molecules came from, but we essentially needed to build them,” Carney said of their study.
“At first the process is sort of slow,” Carney said, “but after the first couple molecules you can start to make them fairly quickly. So by the end of the project, the synthesis was streamlined pretty well so we could make larger quantities.”
Carney and Sello synthesized the ADEPs at the University, but sent their compounds to MIT Professor of Biology Robert Sauer’s lab to analyze how they interact with ClpP, Sello wrote in an email to The Herald.
Signficance of ADEPs
Sello said he and his colleagues’ compounds were “even more potent” than the ADEPs previously created.
There was an innovation gap in antibiotic drug development from 1960 to 2000, Sello said. “We have been depending on old classes of structure type” for antibacterial drugs.
“The Sello lab has (made) a significant advance in moving (ADEPs) closer to clinically viable compounds,” wrote Gerry Wright, director of the Michael G. DeGroote Institute for Infectious Disease Research at McMaster University who was uninvolved in the study, in an email to The Herald. “We’ve not seen a really new chemical scaffold and target in antibiotics in over 25 years, so getting this (much) closer to the clinic is fantastic.”
Future of ADEPs
Researchers should next test whether ADEPs have a similar impact on bacterial pathogens when present in an animal host, wrote Michael Thomas, an associate professor of bacteriology at the University of Wisconsin at Madison who was uninvolved in the study, in an email to The Herald.
“We have been working on pushing this forward,” Sello said. Experiments infecting mice with bacteria and trying to cure them with ADEPs have been promising, he added.
Carney said ADEPs in high concentrations have not appeared lethal to mice.
Researchers should also examine whether ADEPs are toxic to humans, said Jon Clardy, a professor of biological chemistry and molecular pharmacology at Harvard Medical School who was uninvolved in the study.
“Really getting a full grasp on the side effects of these molecules … won’t really be known until clinical trials,” Carney said. “Hopefully we’ll get there.”
The research team is also investigating other chemical structures that might have similar effects to ADEPs, Carney said. This is important in case ADEPs don’t turn out to be successful in humans, he added.
ADVERTISEMENT
