New synthetic molecule can outsmart resistant bacteria

An estimated 2.8 million people in the US contract infections each year from antibiotic-resistant bacteria. according to to the US Centers for Disease Control. More than 35,000 of them die.

Despite the rising toll – and the prospect of one final increase of deaths from superbugs – the development of new antibiotics has not kept pace with the threat. A new drug that can combat Gram-negative bacteria, a particularly hardy species with inner and outer membranes that are difficult for antibiotics to cross, has not appeared on the market for fifty years.

So when a new compound comes onto the scene with a decent chance of eventually becoming one of these much-needed drugs, scientists say it's a big deal.

Researchers from Harvard and the University of Illinois at Chicago have created a new molecule that effectively destroys multiple types of bacteria when tested on animals. The organisms on the hit list include strains of Staphylococcus aureus, Escherichia coli and other pathogens that have become resistant to most antibiotics currently available.

The new molecule, called cresomycinwas described Thursday in the journal Science.

Cresomycin is not yet a drug, nor is it anywhere near ready for human clinical trials. But it represents a promising step toward new treatments that a nonprofit dedicated to combating superbugs gave its Harvard creator $1.2 million this week to develop cresomycin and similar substances into new oral antibiotics.

“I have never been so optimistic or enthusiastic about a project,” he says Andreas Myersthe Harvard University chemist whose laboratory developed the molecule.

Cresomycin belongs to a class of antibiotics known as boosted lincosamides. It works by targeting a bacterium's ribosome, the tiny protein factory found in every living cell.

“Ribosomes can be thought of as a molecular 3D printer,” he says Yuri Polikanova structural biologist at the University of Illinois at Chicago and co-author of the paper.

Just as these machines use plastic molecules to construct objects of any shape, ribosomes take genetic information from RNA and use it to expel proteins.

Because proteins are essential for virtually all cellular activity, ribosomes are vital to bacteria. That's why many antibiotics are designed to combat them.

But bacteria are constantly evolving – embracing new adaptations that help them thwart our attempts to kill them. In some cases, bacteria do this by inserting a small chemical dab, known as a methyl group, into the ribosome. When an antibiotic tries to bind to the ribosome, that methyl group repels it.

The methyl group acts like a small thumbtack on the chair that the antibiotic was hoping to take, Polikanov said.

“It's not very comfortable to sit when a needle pricks you,” he said.

But unlike previous antibiotics, cresomycin binds so tightly to the ribosome that it essentially negates the effect of the methyl group.

Returning to the pushpin analogy, Polikanov said that the molecule sits on its ribosome seat with so much force that it drives the nail into the seat. The ribosome's best defense is neutralized, allowing cresomycin to continue its bactericidal work.

In test tubes, cresomycin proved to be much more effective than currently available antibiotics at inhibiting the growth of several types of bacteria. These include a nasty bug called carbapenem resistant Acinetobacter baumannii that often occurs in hospitals, E.coli And Neisseria gonorrheathe bacteria that causes gonorrhea.

Researchers then took twenty mice and deliberately infected them methicillin resistant S. aureus, better known as MRSA. Half of the mice received four injections of cresomycin over the course of a day, the other half received injections without the active substance.

All but one of the mice that received no treatment were dead two days later. In contrast, all ten mice given cresomycin were still alive seven days after treatment.

In the Science article, the authors were quick to note that cresomycin is not yet ready for human clinical trials.

The Harvard lab manufactured more than 60 molecules in its search for one molecule as effective as cresomycin, and that represents only a small fraction of the “exponentially larger numbers” of possible variations they could make, Myers said. As researchers continue their work, they may be able to find an even better candidate for eventual drug development.

But even at this stage, cresomycin represents an exciting possibility, according to experts not involved in the work.

“Probably about one in a thousand projects gets to the level he's talking about,” he said Richard Alm, chief scientific officer at the Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator, or CARB-X, which earned Myers the $1.2 million grant. Of the potential drugs that reach the stage of development that cresomycin has reached, Alm estimated that one in 30 to 40 will eventually have enough positive data to gain approval from the U.S. Food and Drug Administration.

CARB-X is a global nonprofit organization committed to accelerating the development of new antibiotics. It has awarded nearly 100 grants to date to companies and academic institutions working to treat, prevent or diagnose antibiotic-resistant infections. Its headquarters are at Boston University, the accelerator financed by the governments of the US, UK, Canada and Germany, as well as the Bill and Melinda Gates Foundation, Wellcome Trust and the Novo Nordisk Foundation.

Antibiotic development has stalled in part because they are not as potentially lucrative as other drugs, Alm said. They are not intended to be taken long-term, like medications for chronic conditions such as diabetes or high blood pressure. And doctors want to use the most powerful drugs as rarely as possible, to give bacteria less chance of developing resistance to them.

All that makes it a lot harder to recoup the costs of producing an effective antibiotic, Alm said. Efforts like CARB-X are an attempt to keep the pipeline from drying up.

“If your house is on fire, you don't have time to buy a fire truck, hire firefighters and train them to come and put out your fire. You need them ready to go,” Alm said. “It's the same with antibiotics. If you go to the hospital and you get a superbug, you need an antibiotic that is on the shelf.”

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