Study aims to identify new compounds in the fight against antibiotic resistance

Summary: Researchers have discovered a compound that has the ability to penetrate the barriers used by Gram-negative bacteria to fight antibiotics, injure bugs and prevent them from spreading disease. .

While scientists around the world are waging a war against a new and deadly virus, a lab at the University of Colorado Boulder is working on new weapons to fight a new kind of viral threat. Another possibility: a wave of antibiotic-resistant bacteria, which, if left unchecked, could kill about 10 million people a year by 2050.

Professor of molecular, cellular and developmental biology, who has spent a career researching alternative methods, said Corrie Detweiler, “with the current COVID-19 situation as complex as it is today, we are certainly suffering puts us at risk of increasing antibiotic resistance, so it’s more important right now that we find alternative treatments.”

In a paper published Friday in the journal PLOS Pathogens, Detweiler and her team publish their latest discovery — a chemical compound that may work synergistically with the innate immune system. of the host to penetrate the cell barrier that bacteria use to fight antibiotics.

Along with other recently published discoveries, the authors say, these studies could create a new arsenal of weapons against what could become a threat to public health.

“If we don’t solve the problem of finding new antibiotics or somehow make the old antibiotics work again, we will face increasing the risk of massive death by infectious agents that we thought were eradicated decades ago,” he said. “This study offers a completely new approach and may point to a direct route to new drugs that are more effective and have fewer side effects.”

In the United States alone, about 35,000 people die each year from infections that cannot be treated because they are already resistant to available drugs. And an uncountable number are suffering from life-threatening exacerbations associated with easily treatable conditions such as streptococcal infections, urinary tract infections and pneumonia. The authors note that, by 2050, the number of deaths from drug-resistant bacteria will likely be higher than from cancer.

“Because current antibiotics are poorly adapted and ineffective, our risk basically goes back to 100 years ago, when a small infection meant death,” Detweiler said.

The current pandemic has taken a toll on this, she added, because many patients do not die from the COVID-19 virus itself, but from a secondary infection that is difficult to treat.

Meanwhile, she, through other researchers, worries that using multiple antibiotics to prevent or treat those secondary infections when needed could increase the risk of drug resistance.

Most of the antibiotics in use today were developed in the 1950s, and since then pharmaceutical companies have only focused on developing other, more profitable drugs.

To combat this problem, Detweiler’s lab has developed a technique called SAFIRE for screening for new types of small molecules that work differently from older drugs.

In a study of 14,400 volunteers screened from a library of available chemicals, SAFIRE identified 70 promising ones.

Her new report centers around “JD1,” which exhibits exceptional penetration efficiency against what we know as “Gram-negative bacteria.” This is a bacterium with a very strong outer membrane that prevents antibiotics from entering the cell, and an inner membrane that provides support, bacteria of this class (including Salmonella and E.coli) was basically difficult to treat.

But unlike other drugs, JD1 has the advantage by cooperating with the host’s own innate immune system to attack the outer membrane of the bacteria, and at the same time penetrate 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 own innate immune response,” says Detweiler.

In laboratory and rodent experiments, JD1 reduced the survival and spread of a Gram-negative bacteria called Salmonella enterica by 95%. But at the same time, when damaging bacterial cell membranes, JD1 was unable to penetrate the solid cholesterol layer that surrounds the cell membrane of a mammalian host.

“Bacteria are very vulnerable to JD1 but our cells are not,” she says, so it should be noted that as a result, side effects may be negligible.

Further studies are underway to explore JD1 and other similar compounds.

Meanwhile, Detweiler mentioned a support company to help commercialize other pump-inhibiting compounds, called “efflux pumps,” that the bacteria use. to pump antibiotics out of their own cells.

“The reality is, evolution will always be smarter than all the scientists put together, and bacteria will continue to evolve to resist what we use to fight them,” she said. “We cannot rest on victory. We need to be ready to solve the problem at all times.”

Link to original post: https://www.sciencedaily.com/releases/2020/12/201223125726.htm

Article source: Materials provided by University of Colorado at Boulder. Written by Lisa Marshall.

Reference sources for journals:

Jamie L. Dombach, Joaquin LJ Quintana, Toni A. Nagy, Chun Wan, Amy L. Crooks, Haijia Yu, Chih-Chia Su, Edward W. Yu, Jingshi Shen, Corrella S. Detweiler. A small molecule that mitigates bacterial infection disrupts Gram-negative cell membranes and is inhibited by cholesterol and neutral lipids. PLOS Pathogens, 2020; 16 (12): e1009119 DOI: 10.1371/journal.ppat.1009119

Translated by: Quoc Dung

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