Researchers have found a new way to kill antibiotic-resistant bacteria. The new approach disarms their natural defense mechanism, making existing antibiotics more deadly.
The study, conducted in laboratory dishes and mice, offers a promising strategy to break down so-called superbugs without having to make brand new antibiotics.
“You want to make the existing antibiotics with good safety profiles more potent,” and using a few newly discovered chemicals, the research team did just that, said senior author Evgeny Nudler, professor of biochemistry at New York University Grossman. School of Medicine and an investigator at the Howard Hughes Medical Institute.
In the new study published Thursday (June 1
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Specifically, the enzyme produces hydrogen sulfide, a compound that protects bacteria from oxidative stress or an accumulation of free radicals. So the team sifted through more than 3 million small molecules to find chemicals that would block CSE without interacting with mammalian cells, and they found three strong candidates.
In laboratory dishes, the newly found molecules made bactericidal antibiotics two to 15 times more potent against the microbes depending on the antibiotic used and the measured bacterial strain. One of the small molecules also improved the survival of antibiotic-treated mice that had been infected with both S. aureus or P. aeruginosa.
Given that the study was conducted in rodents in the laboratory, “moving into a human system is, you know, the huge next step,” said Thien-Fah Mah, professor and director of the Microbiology Graduate Program at the University of Ottawa was not involved in the research. And as with all new drug-like molecules, more research is needed to find out which dose and route of administration would be the safest and most effective in humans, Mah told WordsSideKick.com.
But given that most bacterial species use this defensive tactic, targeting hydrogen sulfide production could be a “real game changer” in the fight against antibiotic resistance, Mah wrote in a comment, also published June 10 in the journal Science.
Long road to discovery
The road to the current study began many years ago when a 2007 report in the journal Cell introduced the idea that all bactericidal antibiotics can trigger cell death in the same way, Mah said. “At the time … that kind of leaked out of what we were all thinking,” because each class of bactericidal antibiotics targets different parts of the bacterial cell, so it’s counterintuitive to think that they work in the same way to eventually kill microbes, she said.
For example, some bactericidal drugs are targeted at a cell exterior wall, while others disturb its protein-fabrik, ribosome. But the 2007 paper suggested that all of these substances, after hitting their primary targets, trigger a common secondary effect: They push bacteria to produce “reactive oxygen species,” also known as free radicals, highly reactive molecular destructive spheres that can severely damage DNA. and proteins if they are not immediately defused.
After this work, Noodles and his colleagues discovered one of the bacterium’s natural defense mechanisms against reactive oxygen species: hydrogen sulfide. According to their report, published in 2011 in the journal Science, the team searched the genomes of hundreds of bacteria and found that they shared common gener the code for hydrogen sulphide – producing enzymes with S. aureus and P. aeruginosa primarily using CSE. They reported that hydrogen sulfide increased the production of antioxidant enzymes in the bacteria, which convert free radicals into non-toxic molecules, while suppressing the production of reactive oxygen species.
They also found that deletion or deactivation of the enzymes in bacteria made them “very sensitive” to a wide range of antibiotics. These sensitized bacteria died of oxidative stress caused by an accumulation of reactive oxygen species. At the time, the team wanted to find “inhibitors” that could bind and inactivate bacterial enzymes in an infected person.
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“If we combined these inhibitors with antibiotics … we could make these antibiotics more potent,” Noodles told WordsSideKick.com. But “it was very difficult to find the inhibitors that target these enzymes that were specific for bacteria,” he noted.
Mammalian cells also produce hydrogen sulfide, which means that human cells are also dependent on the compound; in humans, hydrogen sulfide acts as a signaling molecule and interacts with many tissues, from the brain to smooth muscle. Both human cells and bacterial cells use CSE to make hydrogen sulfide, but the human and bacterial CSE come in slightly different flavors. The team wanted to find molecules that would show a strong preference for the bacterial CSE, both to ensure that the chemicals would be potent against bacteria and to avoid unintended side effects on mammalian cells.
To do so, they thoroughly studied the structure of human, bacterial, and other versions of CSE to find an attractive target for their molecules to adhere to. Eventually, they found a “nice pocket” on the bacterial CSE that a small molecule could slide into and alter the activity of the enzyme, Nudler said.
“What they have done is that they actually identified something that is unique to the bacterial enzyme and is not present in the human enzyme … so this is specific to bacteria,” Mah said. After finding a bull-eye to aim at, the team began work on making their weapons. They ran a virtual screen with approx. 3.2 million commercially available small molecules to determine which would fit in their chosen pocket. Three stood as promising choices and reached the next round of experiments.
By reducing the production of hydrogen sulfide, the inhibitors not only increased the effect of antibiotics against bugs, but also suppressed a phenomenon known as “bacterial tolerance.”
Unlike antibiotic resistance, where bacteria develop in ways that make them less susceptible to drugs, tolerance describes when bacteria reject their metabolism in the face of stress and go into a somewhat dormant state. In this state, the cells stop multiplying and reduce their energy consumption. Because many antibiotics work by causing bacteria to short-circuit as they multiply, tolerance keeps the bacteria alive until the antibiotics are gone. This means that some bacterial cells can linger even after an infected person has completed a complete course of antibiotics, and if their immune system is not equipped to handle the remnants, chronic infection can set in, Nudler said.
However, in their experiments, the authors found that the inhibitors stopped many bacteria from switching to this protective state. “We demonstrate that hydrogen sulfide clearly has a large impact on tolerance,” Nudler said. At the moment, “there is no drug that specifically targets … this tolerance phenomenon,” he added, suggesting that this could be a new treatment route.
That said, “from a mechanistic point of view, it is still not entirely clear how inhibition of hydrogen sulfide leads to the various effects observed,” said Dr. Dao Nguyen, associate professor of microbiology and immunology at McGill University in Montreal, who was not involved in the study. Noodles reiterated the mood, noting that he and his colleagues plan to further investigate the role of hydrogen sulfide in tolerance.
The team also needs to decide if they need to adapt the molecules to make them optimally effective for humans, not just mice, and to determine the best route of administration, Nguyen said. “If the inhibitors could be developed into safe and effective drugs, one could imagine that they would be used in combination with existing antibiotics to treat … chronic infections where current antibiotics are not very effective,” she said.
Originally published on WordsSideKick.com.