Wednesday , September 28 2022

To find the next antibiotic, scientists are giving new targets new drugs


With antibiotic-resistant bacteria on the rise, scientists are urgently trying to find drugs that will work against persistent infections. But inventing new ones should not be the only strategy.

A recent survey published in Proceedings of the National Academy of Sciences found that they could restore Biononol, a medicine previously used to treat parasitic infections in horses, to kill antibiotic-resistant bacteria, including MRSA, a common hospital infection.

The results not only suggest promising treatment for this infection, but hint at new ways for scientists to tackle the problem of antibiotic resistance by exploring new uses of old drugs and also using them in combination with traditional antibiotics.

"There is a lot of effort these days to try and change compounds to meet the challenge of antibiotic resistance," said Gary Wright, a professor in the Department of Biochemistry and Biomedical Sciences at McMaster University in Canada who studies how bacteria become antibiotic resistant.

"It's nice to see a result like this because it tells us that there are many interesting molecules, even molecules that were used for something else," says Wright, who did not participate in the study.

The work was a collaboration between researchers at Brown, Emory and Harvard University. Their idea was to find an existing drug that targets the membrane of the bacteria, part of the bacteria that most antibiotics do not attack.

The membrane "is the only goal you can achieve, after which bacteria really can't escape," says Dr. Eleftherios Milonakis, a professor of infectious diseases at Brown University and author of the study.

MRSA or methicillin resistant Staphylococcus aureusThe bug is responsible for some cases of pneumonia as well as skin and blood infections. Bacteria are especially dangerous for elderly or ill patients who do not have a strong immune system.

MRSA infections contain bacteria, known as persists, that protect against antibiotics, turning them into "couch potatoes," said William West, an associate professor of chemistry at Emory University and one of the study's authors. They switch to low-energy, dormant states, allowing them to escape the onslaught of ordinary antibiotics that target bacteria's ability to grow and multiply.

A membrane that controls what enters and exits bypasses all bacteria inside. The membrane is always there, even if the bacteria are not actively developing. This makes the bacterial membrane an attractive point from which the attack proceeds.

Scientists began by looking for existing drugs that could penetrate the MRSA membrane.

They screened more than 80,000 known drugs. They infected worms known as C. elegans with MRSA and then tried the drugs to see which ones would kill the MRSA bacteria, but not the worms. They found 185 drugs that passed through this screen, but only a few, including biononol, could penetrate the membrane of the persistent bacteria.

Scientists then showed that bitionol can kill MRSA persists in a laboratory dish for 24 hours, while conventional antibiotics such as daptomycin and linezolid cannot.

Although bitionol is known to have some antibacterial activity, the results of this study indicate that "it is actually much more powerful than the previous report," said Megan Blacklidge, a chemistry assistant at Ms Point University, who is researching treatment for MRSA. Blackledge did not participate in this study.

But researchers have found a potential problem with biononol – it is devastating. When used in high doses, it causes the bacteria to open and die. In order for bioionol to be a safe antibiotic treatment for humans, scientists have had to show that it can penetrate only the membranes of bacteria, but not those of human cells.

Unlike the membranes of bacteria, the membranes of human cells and those of other mammals contain cholesterol, which makes the membrane more tightly packed and difficult to penetrate. Using computer simulations, scientists have shown that bithionol can only penetrate the membranes of bacteria but not in mammalian cells.

Another problem with antibiotics that kill bacteria by breaking them open is that they can generate resistance. This is because the bacteria adapt to attack and can change in ways that reduce the effectiveness of antibiotics.

The researchers designed an experiment to determine if the drug could work without bursting the membranes of the bacteria. The researchers tried the drug in mice that had MRSA infection in their hips. They use a lower dose of bitionol, which cannot kill MRSA, is retained on its own and combined with the traditional antibiotic gentamicin. The combination eliminates 90% of MRSA thigh infection, while other common antibiotics do not.

The lower dose of bithionol penetrating the MRSA membrane is retained, but instead of destroying the membrane open, it loosens it to allow gentamicin to kill the bacteria inside.

The advantage of bitionol is that it can be used at a concentration at which it is unable to kill MRSA on its own and combine it with traditional antibiotics that can finish the job. For example, gentamicin is not usually used to treat infections in humans, since the dose it is used to can cause kidney damage. But by combining it with bitionol, the researchers were able to use gentamicin at lower concentrations.

"I really think the future for overcoming antibiotic resistance is those combination therapies where we can use lower doses than the more toxic antibiotics," West says.

Wright says there is still a chance that the bacteria may become resistant to bitionol. "In my opinion, there is no such thing as a compound that bacteria can't resist," Wright says. "It is not obvious to me how it will happen, but I am quite sure that at some point it will happen."

West agrees. "I will hesitate to say it [bithionol] I could never have the resistance created against him, but the mechanism by which he works … makes me more optimistic. "

Louisa Torres is a contributor to the AAAS Mass Media at the NPR Science Office. She is on Twitter at @luisatorresduq

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