Researchers say they have created a new antibiotic to treat the bacterium Acinetobacter baumannii.
It is known for its resistance to many types of antibiotics, which can complicate treatment and lead to persistent and potentially fatal infections, he says CNN.
Acinetobacter baumannii can cause serious infections in the lungs, urinary tract, and blood, according to the US Centers for Disease Control and Prevention. This bacteria is resistant to a class of broad-spectrum antibiotics known as carbapenems.
Carbapenem-resistant Acinetobacter baumannii, also called CRAB, topped the World Health Organization’s list of antibiotic-resistant “priority pathogens” in 2017. In the United States, the bacterium caused about 8,500 infections among hospitalized patients and 700 deaths that year, according to the most recent data provided by the CDC. The prevalence of CRAB in hospital-acquired infections in the US is around 2%. However, it is more prevalent in regions such as Asia and the Middle East, causing up to 20% of infections in intensive care units globally.
Bacteria multiply in medical environments such as hospitals and nursing homes. People at greatest risk of infection include those with catheters, those who are ventilator-dependent, or those who have open wounds from surgery.
Associated pathogens are so resistant that researchers say the US Food and Drug Administration hasn’t approved a new class of antibiotics to treat them in more than 50 years, according to a study published Jan. 3 in the journal Nature.
However, researchers from Harvard University and the Swiss health care company Hoffmann-La Roche say that the new antibiotic, zosurabalpin, is showing efficacy in eradicating the bacterium Acinetobacter baumannii. Zosurabalpin is in a distinct chemical class and takes a unique approach to its mode of action, said Dr. Kenneth Bradley, global head of infectious disease discovery at Roche Pharma Research and Early Development and one of the researchers.
“This is a novel approach, both in terms of the compound itself and the mechanism by which it kills bacteria,” he said.
Acinetobacter baumannii is a gram-negative bacterium, characterized by the presence of inner and outer membranes, which confers a difficult resistance to treatment. The objective of the research was to identify and adjust a molecule capable of crossing the two layers of membranes and eliminating the bacteria.
According to Bradley, “These two membranes form a formidable barrier against the penetration of molecules such as antibiotics.”
The process of developing zosurabalpin began by examining about 45,000 small antibiotic molecules called macrocyclic peptides, and researchers identified molecules that could inhibit the growth of various types of bacteria. After years of optimizing the potency and safety of a small number of compounds, a modified molecule was arrived at.
Zosurabalpin stops the proliferation of Acinetobacter baumannii by blocking the movement of large molecules called lipopolysaccharides to the outer membrane, where they are essential for maintaining membrane integrity. This process causes these molecules to accumulate inside the bacterial cell, generating toxic levels that lead to cell death.
According to the study, zosurabalpin demonstrated efficacy against more than 100 clinical samples of CRAB tested. The researchers found that the antibiotic significantly reduced the levels of the bacteria in mice that developed CRAB-induced pneumonia. It also prevented the death of mice with sepsis caused by these bacteria.
“Drug discovery that targets harmful gram-negative bacteria is a long-standing challenge because of the difficulties in getting molecules to cross bacterial membranes to reach targets in the cytoplasm,” the researchers wrote. “Successful compounds must usually possess a certain combination of chemical characteristics.”
Zosurabalpin is currently in phase 1 clinical trials evaluating the safety, tolerability and pharmacology of the molecule in human subjects, according to the study authors. However, there remains a considerable threat to public health worldwide from antimicrobial resistance, which is due to the lack of effective treatments, warns Dr Michael Lobritz, Global Head of Infectious Diseases at Roche Pharma Research and Early Development, who was involved in research.
Antimicrobial resistance occurs when organisms such as bacteria and fungi evolve enough to survive drugs designed to kill them.
In 2019, an estimated 1.3 million deaths globally were directly attributable to antimicrobial resistance, according to a 2022 review published in The Lancet. In comparison, HIV/AIDS and malaria caused 860,000 and 640,000 deaths respectively that year. In the United States, more than 2.8 million antimicrobial-resistant infections occur annually, leading to more than 35,000 deaths, according to the CDC’s 2019 Antibiotic Resistance Threats Report.
Even though more research is needed and zosurabalpin is still several years away from clinical use, the development is extremely promising, according to Dr. César de la Fuente, presidential assistant professor at the University of Pennsylvania.
“It could be many years,” said de la Fuente, who was not involved in the new research. “However, I think from an academic perspective, it’s exciting to see a new type of molecule that kills bacteria in a different way. We definitely need new ways of thinking about antibiotic discovery, and I think this is a good example of that.”
The researchers suggest that the strategy used to prevent the growth of Acinetobacter could also be useful in treating other treatment-resistant bacteria, such as E. coli.
Dr. Bradley explains that zosurabalpin works by blocking the formation of the outer membrane, a process common to all gram-negative bacteria. By understanding the biology behind this action, future researchers could develop ways to prevent the growth of other bacteria using modified molecules.
The researchers point out that the downside of this approach is that the modified molecule will only be effective against certain bacteria for which it was designed. However, Dr. de la Fuente suggests that this method of tailoring molecules to target specific bacteria could have significant benefits for our overall health, as many broad-spectrum antibiotics are known to affect beneficial bacteria, especially in the gut and on the skin .
“For decades, we’ve been obsessed with creating or discovering broad-spectrum antibiotics that kill everything,” de la Fuente noted. “Why not try to come up with specific, more targeted antibiotics that only target the pathogen that’s causing the infection and not all the other things that might be good for us?”
2024-01-10 10:37:12
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