Scientists have discovered new ways to kill antibiotic-resistant bacteria. The new approach disarms those natural defenses and makes existing antibiotics more deadly.
This study, conducted on laboratory dishes and mice, provides a promising strategy for eliminating so-called super bugs without the need to create brand new ones. Antibiotics..
“We want to make existing antibiotics with a good safety profile stronger,” said Evgeny Nadler, a senior author of biochemistry at New York University’s Grossman School, helping with some newly discovered chemicals. Borrowed and said he did exactly that. Researcher at the School of Medicine and Howard Hughes Medical Institute.
The new study was published in the journal on Thursday (June 10th) Science, The team aimed Staphylococcus aureus And Pseudomonas aeruginosa, Two Bacteria It exhibits widespread resistance to multiple drugs and is ranked as one of the leading causes of nosocomial infections. These bacteria rely on an enzyme called cystathionine gamma lyase (CSE) to not only slow the growth of the bacteria, but also counteract the toxic effects of bactericidal antibiotics, which are drugs that kill the bacteria.
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Specifically, the enzyme produces compounds that protect the bacteria from hydrogen sulfide, oxidative stress, or the accumulation of free radicals. So the team screened over 3 million small molecules to find chemicals that block CSE without interacting with mammalian cells, and found three promising candidates.
In the laboratory dish, the newly discovered molecule made bactericidal antibiotics 2 to 15 times more potent against microorganisms, depending on the antibiotic used and the bacterial strain targeted.One of the small molecules also improved the survival rate of antibiotic-treated mice infected with either Staphylococcus aureus Or Pseudomonas aeruginosa..
Thien-Fah Mah, a professor and director of the University of Ottawa’s Graduate School of Microbiology program, said, “Transitioning to the human system is a big next step, given that the research was done in laboratory rodents. That’s it. ” Those who were not involved in the research. And, like other new drug-like molecules, more research will be needed to identify which doses and routes of administration are the safest and most effective for people, Marr said. I told live science.
However, given that most bacterial species use this defensive tactic, aiming for hydrogen sulfide production could be a “true game changer” in the fight against antibiotic resistance. Mah writes in the comments. Science..
A long way to discover
The road to current research began a few years before it was reported in the journal in 2007. cell According to Ma, he introduced the idea that all bactericidal antibiotics can cause cell death in the same way. “At that point … it blew off the lid of what we all thought.” Because each class of bactericidal antibiotics targets different parts of the bacterial cell, they eventually kill. It’s counterintuitive to think that it works the same for microorganisms, she said.
For example, some disinfectants Outer wall of cell, While others confuse it protein-Building factory, ribosome. However, a 2007 paper suggests that all of these drugs cause a common side effect after achieving a key goal. It pushes bacteria to produce “reactive oxygen species,” also known as free radicals, highly reactive molecular-destroying balls that can cause serious damage to DNA. Protein if not diffused immediately.
Following this study, Nudler and his colleagues discovered hydrogen sulfide, one of the bacteria’s natural defense mechanisms against reactive oxygen species.According to their report, it was published in the journal in 2011. Science, The team scrutinized the genomes of hundreds of bacteria and found that they had something in common gene It encodes a hydrogen sulfide-producing enzyme and Staphylococcus aureus And Pseudomonas aeruginosa I mainly use CSE. They reported that hydrogen sulfide stimulated the production of bacterial antioxidant enzymes, converting free radicals into non-toxic molecules and at the same time suppressing the production of reactive oxygen species.
They also found that by removing or disabling bacterial enzymes, they became “very sensitive” to a wide range of antibiotics. These sensitized bacteria died from oxidative stress caused by the accumulation of reactive oxygen species. At that point, the team wanted to find an “inhibitor” that could bind and neutralize the infected bacterial enzyme.
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“Combining these inhibitors with antibiotics … can make these antibiotics more potent,” Nudler told Live Science. However, “it is very difficult to find inhibitors that target these bacteria-specific enzymes,” he said.
Mammalian cells also produce hydrogen sulfide. In other words, human cells also depend on this compound. In humans, hydrogen sulfide acts as a signaling molecule and interacts with many tissues, from the brain to smooth muscle. Both human and bacterial cells use CSE to make hydrogen sulfide, but human and bacterial CSE have slightly different flavors. The team wanted to find a molecule that strongly favors bacterial CSE to ensure that the chemical is potent against the bacterium and to avoid unintended side effects on mammalian cells.
To do so, they extensively studied the structure of humans, bacteria, and other versions of CSE to find attractive targets for molecules to latch. Eventually, they found a “nice pocket” in the bacterial CSE where small molecules could slip and alter enzyme activity, Nadler said.
“What they did was identify something that was really specific to bacterial enzymes and not to human enzymes … so this is specific to bacteria,” Ma said. After finding the eyeballs to aim for, the team set about making weapons. They ran about 3.2 million small molecule virtual screens on the market to determine which one would fit in the pocket of their choice. Three stand out as promising options and proceeded to the next experimental round.
By suppressing the production of hydrogen sulfide, inhibitors not only increased the effectiveness of antibiotics against insects, but also suppressed a phenomenon known as “bacterial resistance.”
Unlike antibiotic resistance, which evolves to make bacteria less susceptible to drugs, resistance represents the time when bacteria face stress, slow down metabolism, and enter a slightly dormant state. In this state, cells stop growing and use less energy. Many antibiotics work by short-circuiting the bacteria during growth, so resistance keeps the bacteria alive until the antibiotics are gone. This means that some bacterial cells may remain after the infected person completes a full course of antibiotics, and if the immune system is not equipped to handle the rest, a chronic infection. May begin, Nadler said.
However, in their experiments, the authors found that the inhibitor prevented many bacteria from switching to this protected state. “Hydrogen sulfide clearly shows a significant impact on resistance,” says Nudler. Currently, “… there is no drug that specifically targets this resistance phenomenon,” he adds, suggesting that this may be a new path of treatment.
However, “how inhibition of hydrogen sulfide leads to the various observed effects is not yet completely clear from a mechanistic point of view,” said Associate Professor of Microbiology and Immunology, McGill University. Dr. Dao Nguyen said. Montreal who was not involved in the study. Reflecting emotions, Nudler said he and his colleagues plan to further investigate the role of hydrogen sulfide in resistance.
The team also needs to fine-tune the molecule to determine if it needs to have optimal effects not only in mice but also in humans, and to determine the optimal route of administration, Nguyen said. “If inhibitors can develop into safe and effective drugs, imagine that current antibiotics will be used in combination with existing antibiotics to treat less effective chronic infections. You can, “she said.
Originally published in Live Science.
New discoveries may help eliminate drug-resistant bacteria
Source link New discoveries may help eliminate drug-resistant bacteria