As scientists around the world wage war on a new, deadly virus, a University of Colorado Boulder lab is working on a new weapon to combat a different microbial threat: a growing tide of antibiotic-resistant bacteria that, if left unchecked, could kill an estimated 10 million people annually until 2050..
“The situation with COVID-19 definitely puts us at risk due to increased antibiotic resistance, so it’s now more important than ever to devise alternative treatments,” said Corrie Detweiler, a professor of molecular, cellular and developmental biology who has spent her career looking for these. alternative.
In a paper published Friday in the journal PLOS pathogens, Detweiler and her research team reveal their latest discovery – a chemical compound that works with the host ‘s innate immune response to cross cellular barriers that help bacteria resist antibiotics.
Along with other recently published discoveries, the authors say, the discovery could lead to a new arsenal to combat what could be the next major public health hazard.
“If we don’t solve the problem of finding new antibiotics or somehow make old antibiotics work again, we will see a sharp increase in deaths from bacterial infections that we thought we beat a few decades ago,” Detweiler said. “This study offers a whole new approach and could point the way to new drugs that work better and have fewer side effects.”
In the United States alone, 35,000 people die each year from bacterial infections that cannot be treated because they have grown resistant to existing drugs. Countless others suffer from life-threatening attacks from diseases that can be easily cured, such as strep throat, urinary tract infections and pneumonia. By 2050, the authors note, there could be more deaths due to antibiotic resistance than from cancer.
“As our existing antibiotics are less adaptable and effective, we risk basically going back to a period 100 years ago, when even a minor infection could mean death,” Detweiler said.
The pandemic has shed even more light on the problem, she notes, because many patients do not die from the virus itself but from difficult-to-treat secondary bacterial infections.
Meanwhile, she and other scientists worry that increased use of antibiotics to prevent or treat these secondary infections, although sometimes needed, could worsen resistance.
Most of the antibiotics used today were developed in the 1950s, and pharmaceutical companies have since reduced their research in favor of more profitable ventures.
To power the pipeline, Detweiler’s lab developed a technique called SAFIRE to test new small molecules that act differently from older drugs.
Out of 14,400 candidates reviewed from the library of existing chemicals, SAFIRE identified 70 that are promising.
The new paper focuses on “JD1”, which seems to be particularly effective in infiltrating so-called “gram-negative bacteria”.
With a solid outer membrane that prevents antibiotic access to the cell and another inner membrane that provides buffer, these bacteria (including Salmonella i E. coli) are essentially difficult to treat.
But unlike other drugs, JD1 takes advantage of the host’s initial immune attack on that outer bacterial membrane, then sneaks inside and goes after the inner membrane.
“This is the first study to show that you can target the inner membrane of gram-negative bacteria by exploiting the host’s innate immune response,” Detweiler said.
In laboratory experiments and experiments on rodents, JD1 reduced the survival and spread of gram-negative bacteria called Salmonella enterica by 95%.
But while it damaged the bacterial cell membrane, it could not penetrate the fine layer of cholesterol that lined the mammalian host cell membranes.
“Bacteria are vulnerable to JD1 in a way that our cells are not,” Detweiler said, noting that for that reason the side effects would likely be minimal.
Further studies are underway to investigate JD1 and other similar compounds.
Meanwhile, Detweiler has founded a spin-off company that helps commercialize other compounds that act by inhibiting pumps, called “discharge pumps,” which bacteria use to pump out antibiotics.
“The reality is that evolution is smarter than all the scientists combined, and these bacteria will continue to grow to resist what we throw at them,” she said. “We can’t rest on our laurels. We have to keep feeding the pipeline.”