Scientific Strategies to Tackle Antibiotic Resistance

Conventional antibiotics kill or reduce the activity of individual bacteria. Some bacteria develop resistance to these antibiotics, allowing them to grow further and displace those that are not resistant. As a result, the use of antibiotics has led to more and more bacteria becoming resistant to antibiotics. According to the World Health Organization (WHO), about 1.27 million people worldwide died from drug-resistant infections in 2019, and it is expected that the annual death toll from drug-resistant infections could be as high as 10 million by 2050. Scientists are using a variety of strategies to accelerate the development of new antibiotics and slow the spread of resistance.

Reveal new mechanism of antibiotic resistance

Researchers at Baylor College of Medicine have been studying the processes that drive antibiotic resistance at the molecular level, hoping to contribute a solution to this growing antibiotic resistance problem. In a new study, these researchers report a critical first step in promoting resistance to one of the most commonly used antibiotics, ciprofloxacin. The findings point to potential strategies that could prevent bacteria from developing resistance and prolong the effectiveness of old and new antibiotics.

According to co-author Professor Susan M. Rosenberg, previous research by her team has shown that when bacteria are exposed to a stressful environment caused by antibiotics such as ciprofloxacin, they initiate a series of stress responses in order to survive. Ciprofloxacin can induce mutations in bacteria, a process known as stress mutagenesis, which can lead to the development of ciprofloxacin-resistant mutants, making it difficult to clear bacterial infections with ciprofloxacin.

Ciprofloxacin induces DNA double-strand breaks, which accumulate in bacteria and trigger a DNA damage repair response. Research in the Rosenberg lab revealed two key stress responses in the process of stress mutagenesis: the general stress response and the DNA damage response. While previous studies have elucidated some of the downstream mechanisms by which mutation rates rise, this study focuses on the molecular mechanisms that lead to the first step between antibiotic-induced DNA breakage and bacterial initiation of the DNA damage response.

Dr Zhai, first author of the paper, said they had discovered a surprising new molecule that regulates DNA repair. Normally, cells regulate their activity by producing proteins for specific functions. In this case, however, the initiation of the DNA repair response does not depend on the activation of specific protein-coding genes. Instead, the first step involves inhibiting pre-existing RNA polymerase activity, which is key to protein synthesis. This enzyme binds to DNA and transcribes the instructions encoded by DNA into RNA sequences, which are then translated into proteins. Dr Zhai further explained that RNA polymerase plays an important role in regulating the DNA repair process. Under stress conditions, a small molecule called ppGpp is present in bacteria that is able to bind to RNA polymerase through two separate sites that are critical for initiating the repair response and the general stress response. Interference with one of these sites can specifically inhibit the repair activity on the DNA sequence where the RNA polymerase is located.

The findings offer new opportunities to design strategies to disrupt the emergence of antibiotic resistance and help turn the tide on this global health threat. In addition, ciprofloxacin damages bacterial DNA in the same way that the cancer drug etoposide damages human DNA in tumors. This could help develop new tools to fight resistance to cancer chemotherapy drugs.

New antibiotics found in natural products

The discovery of antibiotics once relied on natural products extracted from soil microbes, particularly Actinomyces. Over time, however, antibiotics that can effectively fight new types of bacteria have become harder to find. To break through this bottleneck, researchers are starting to take a fresh look at antibacterial molecules that may have been overlooked in the past. For example, A compound produced by actinomycetes, hygromycin A, is not widely used because it is difficult to enter cells in most microorganisms. However, the researchers found that the compound has specific lethality against the bacterium Borrelia burgdorferi, which causes Lyme disease, a finding that provides an opening for the drug to be redeveloped. Another breakthrough was the discovery of teixobactin, an antibiotic produced by hard-to-culture microbes that kills bacteria by preventing their cell walls from forming. Teixobactin is currently undergoing animal toxicity testing and is expected to enter human trials soon.

Antibiotics at BOC Sciences

Antibiotic production services at BOC Sciences

AI for antibacterial compounds discovery

Artificial intelligence (AI) is playing an increasingly important role in antimicrobial drug discovery. The researchers used AI to screen millions of known compounds to predict which of them might have antibacterial potential. Cesar de la Fuente, a bioengineer at the University of Pennsylvania, used AI to discover antimicrobial peptides in extinct animals. MIT bioengineer Jim Collins, who was concerned about the large size of peptide molecules, further used AI to discover small molecules with antibacterial potential.

With the help of AI, the Collins research team discovered a compound called halicin, and the test results showed that halicin successfully treated mice infected with Acinetobacter baumannii and C. difficile. Acinetobacter baumannii can infect the lungs, wounds, blood and urethra. Clostridium difficile mainly infects the gut. The researchers also used AI to discover the compound abaucin, which specifically targets Acinetobacter baumannii.

Combination therapy for bacterial infections

Combination therapy, or cocktail therapy, is the simultaneous use of multiple drugs against the microbe. This is not an entirely new approach; it has already been used to control the TB bacterium. But this method can find two drugs that work synergistically with each other. In addition, the method can also find some antibacterial synergies that have no antibacterial effect on their own but can help other drugs work better. For example, kaverol, a compound found in strawberries, interferes with the biofilm of Acinetobacter baumannii and sensitises the microbe to sublethal doses of colistin.

Immune regulation reduces antibiotic use

New antibiotics and helper molecules could speed up the race in medicine, but researchers are also seeking ways to slow the spread of resistance in microbes. One way to do this is to improve the clinical treatment of infections, thereby reducing the use of antibiotics. The immune system is able to deal with pathogens in most cases without assistance. By recalibrating the immune response, the body can regain control over the microbes. Researchers at Newcastle University found that when patients get pneumonia as a result of using a ventilator, their white blood cells typically have a diminished ability to engulf microorganisms. The researchers are testing a natural immunomodulator called GM-CSF, which is designed to boost phagocyte function. By reducing the use of antibiotics through this therapy, it is possible to reduce the external pressure on microbes to develop resistance.

Efficient diagnostics slow drug resistance evolution

Rapid and accurate diagnosis of the cause of infection and identification of effective antibiotics can also reduce antibiotic use and slow the evolution of bacterial or viral resistance. Robby Bhattacharya, a molecular microbiologist at the Broad Institute, points out that they rarely encounter biological infections that are completely untreatable. But when people are very sick and test results are delayed, doctors prescribe broad-spectrum antibiotics or try multiple drugs that may accelerate the spread and development of resistance in bacteria or viruses.

John Paulson's team at Harvard Medical School is using microfluidics and microscopy to study how individual microbes grow and divide, and how they respond to treatment. The goal is to diagnose blood samples and analyze antibiotic resistance within an hour.

In June, a similar technique developed by Swedish scientists won a $10 million prize for antibiotic resistance research. The technology can tell in about 45 minutes whether the "culprit" of a urinary tract infection is a bacteria or a virus, and which antibiotic is most effective.

References

1. Zhai, Y., et al. ppGpp and RNA-polymerase backtracking guide antibiotic-induced mutable gambler cells. Molecular Cell. 2023, 83(8): 1298-1310.
2. Dance, A. Five ways science is tackling the antibiotic resistance crisis. Nature. 2024, 632(8025): 494-496.