Dangerous ‘superbugs’ are a growing threat, and antibiotics can’t stop their rise. What can?

Traditional antibiotics drive bacteria toward drug resistance, so scientists are looking to viruses, CRISPR, designer molecules, and protein swords for better treatments.

Bacteria could have entered his skin along with shrapnel from the bomb that exploded at Brussels airport in 2016. Or perhaps the bacteria had adhered to the surgical instruments used to treat his wounds. ta. Regardless, the “superbug” still refuses to be defeated despite being treated with antibiotics for many years.

The woman survived a terrorist attack but was held hostage by Klebsiella pneumoniae, a drug-resistant strain of bacteria that often infects surgical patients in hospitals. Only by combining antibiotics with a new experimental treatment were doctors finally able to rid her of the superbug. Devastating drug-resistant bacterial infections like these are all too common and are a growing threat to global health. In 2019, antibiotic-resistant bacteria directly killed about 1.27 million people worldwide and contributed to an additional 3.68 million deaths. In the United States alone, drug-resistant bacteria and fungi cause about 2.8 million infections and 35,000 deaths each year.

And the problem gets worse:
Seven of the 18 types of bacteria tracked by the Centers for Disease Control and Prevention (CDC) are becoming more resistant to common antibiotics considered essential to maintaining public health. Meanwhile, pharmaceutical companies are slow to create new antibiotics that can kill bacteria. Fewer than 30 antibiotics currently in development target “priority” bacteria, as defined by the World Health Organization (WHO), and most of these drugs are still susceptible to resistance, as are predecessor drugs.

This table of select antibiotic-resistant bacteria demonstrates how rapidly important types of resistance developed after the approval and release of new antibiotics. (Image credit: Centers for Disease Control and Prevention. Adapted by Live Science from the CDC’s “Select Germs Showing Resistance Over Time” Fact Sheet.)

Therefore, some scientists are looking for, in addition to traditional antibiotics, new weapons that do not cause the growth of superbugs. Their emerging arsenal includes bacteria-killing viruses; CRISPR; and bacteria-killing molecules. They hope these experimental treatments, some of which have already been tested on patients, will kill the superbugs without causing drug resistance.

“For me, the vision is to go beyond antibiotics and see more options”. Direct science. But until these new treatments are ready for early use, the world must reduce the overuse and misuse of antibiotics, which experts say is accelerating the rate at which This life-saving medicine becomes obsolete.

How does antibiotic resistance emerge and spread?

(Image credit: Centers for Disease Control and Prevention. Adapted by Live Science from the CDC’s “How Resistance Moves Directly Germ to Germ” Fact Sheet.)

Antibiotics kill bacteria directly or slow their growth, letting the immune system finish the job. These drugs work in many ways: for example, by stopping bacteria from building strong walls or making copies of their DNA. Antibiotics that slow growth often disrupt ribosomes, the protein factories of bacterial cells.

Many antibiotics target precisely the same molecular targets, and the mechanisms of so-called broad-spectrum antibiotics are so common that they act on two main types of bacteria:
Gram-positive and Gram-negative, are distinguished by the composition and thickness of their cell walls. Broad-spectrum antibiotics, in particular, pressure harmful and beneficial bacteria in the body to develop defense strategies that repel or neutralize drugs or alter their targets. Bacteria can acquire such defenses through random DNA mutations or by exchanging “resistance genes” with other bacteria through a process called horizontal gene transfer. By making these gene transfers, bacteria can rapidly spread these mutations to other bacterial populations in the body and the environment.

The overuse of antibiotics in health care as well as in agriculture has created endless opportunities for bacteria to develop resistance, increasing the risk that treatable infections will become dangerous.

Harnessing viruses to fight bacteria.

(Image credit: Graphic made by Olha Pohrebniak via Getty Images. Adapted by Live Science.)

One of the proposed alternatives to antibiotics was designed more than a century ago, before the discovery of penicillin in 1928. Called phage therapy, it uses infectious viruses Bacteria called bacteriophages, or simply “bacteriophages,” typically kill germs by invading their cells. and open them from the inside.

Bacteriophages can also pressure bacteria to abandon key tools in their drug resistance toolkit. For example, a phage called U136B can have this effect on E. coli. To enter E. coli, bacteriophages use an efflux pump, a protein that E. coli commonly uses to pump antibiotics out of the cell. If E. coli tried to modify this pump to escape the phage, it would reduce the bacteria’s ability to excrete antibiotics. And unlike antibiotics, bacteria are unlikely to develop widespread resistance to phage therapy, said Paul Turner, director of the Center for Phage Biology and Therapeutics at Yale University.

Turner and other experts concluded that “if phage therapy were used on a global scale, it would not lead to widespread drug resistance problems in the same way that antibiotic use has led to hey,” he told Live Science.

Here’s why:
Antibiotic resistance has increased significantly due to the misuse and abuse of antibiotics, especially broad-spectrum antibiotics that are effective against many types of bacteria. On the other hand, bacteriophages can have a much narrower target than even narrow-spectrum antibiotics – for example, targeting a protein found in only one or a few strains within a bacterial species.

The target bacteria can still develop resistance to individual phages, Turner said, but by choosing the right combination of phages, scientists can ensure that the Bacterial evolution will come at a cost. This cost may reduce virulence or increase vulnerability to antibiotics.

Designer molecules to kill bacteria.

One approach for killing bacteria is to use lysins, or enzymes that tear open bacterial cell membranes and cause the microbes’ contents to spill out. (Image credit: KATERYNA KON/SCIENCE PHOTO LIBRARY via Getty Images)

In addition to phages and CRISPR, scientists are developing alternatives to antibiotics that exploit bacteria-killing peptides (short chains of protein building blocks) and enzymes, specialized proteins that trigger chemical reactions. learn. These molecules differ from antibiotics because they can kill a very narrow range of bacteria by targeting bacterial proteins that cannot easily gain resistance to their attacks.

Molecules created in the laboratory, called peptide nucleic acids (PNA), are one of the most promising candidates. These modified molecules can be designed to prevent bacterial cells from making proteins essential for their survival. To do this, PNA binds to specific mRNAs, genetic molecules that carry protein-building instructions from the cell’s control center to its protein-building sites. However, PNA cannot enter bacterial cells on its own, so they are often attached to other peptides that easily penetrate bacterial cell walls.

By targeting proteins that cells cannot modify without harming themselves, Beisel explains, PNA can avoid inducing drug resistance. Genetically engineered molecules can also be designed to target proteins that directly contribute to antibiotic resistance, such as drug efflux pumps that remove antibiotics from cells or enzymes that ability to neutralize drugs. By emptying a germ’s resistance toolbox, NAP can then make it vulnerable to standard treatments.

Antibacterial NAP is still being tested in lab dishes and in animals and has not been tested in humans. And scientists must ensure that PNA treatments do not accidentally disrupt human cells or beneficial bacteria.

In addition to peptides like PNA, an enzyme called lysine is another promising treatment option. Lysine is used in nature by phages to open bacteria from the inside. They act like tiny swords that cut through the outer wall of the bacterial cell, spilling out into the cell’s interior. Molecular disruptors are unlikely to promote resistance because bacteria cannot easily modify the essential cell wall components that lysine targets. Lysines kill bacteria rapidly on contact, and they can be very specific, killing some types of bacteria while eliminating others. Additionally, lysine can be modified in the laboratory to change the bacteria they target, increasing their potency and improving their durability in the body.

Several lysins have been in mid- and late-stage human trials involving hundreds of participants, where they were tested as add-on treatments to antibiotics but with mixed results.

Antibiotic stewardship can save lives, in the meantime…

Until these next-generation antibacterial drugs reach the market, immediate steps must be taken to limit the rise of superbugs, preventing the overuse of antibiotics that cause Bacteria to develop resistance from the start.

For example, doctors could be more diligent in confirming that bacteria, not viruses, are the cause of a patient’s infection before prescribing antibiotics, said researcher Dr. Shruti Gohil of the four INSPIRE-ASP trials, a federally funded study aimed at improving antibiotics in hospitals, said. . to use. Other safeguards may include checking your doctor’s prescription to see if a narrow-spectrum drug can be used instead of a broad-spectrum drug or requiring special authorization for the broad-spectrum drug. These steps are essential not just in hospitals but anywhere antibiotics are prescribed, from primary care to dentistry, Gohil said.

Every interaction between doctors and their patients counts. Gohil emphasized that “by reducing individual risk, you anticipate that you will reduce the overall risk at the population level” and ultimately reduce the prevalence of multidrug-resistant bacteria.

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