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Scientists Develop New Antibiotic to Kill Drug-Resistant Bacteria

Scientists have developed a novel antibiotic to combat bacteria resistant to existing antibiotics. The bacteria, Acinetobacter baumannii, causes infections in the lungs, urinary tract and blood and has a high mortality rate.

The US Centers for Disease Control and Prevention (CDC) report that it is resistant to a class of broad-spectrum antibiotics known as carbapenems, and it kills a significant number of people via invasive infection.

In 2017, the World Health Organization released a list of antibiotic-resistant “priority pathogens,” listing Carbapenem-resistant Acinetobacter baumannii (CRAB) in its critical category. The organization describes pathogens of this designation as “ multidrug-resistant bacteria that pose a particular threat in hospitals, nursing homes, and among patients whose care requires devices such as ventilators and blood catheters.”

Data from the CDC shows that the bacteria caused 700 fatalities and 8,500 infections in hospitalized patients in the US that year. Being a Gram-negative bacteria, protected by inner and outer membranes, makes CRAB incredibly difficult to treat. The US Food and Drug Administration has not authorized a new class of antibiotics to treat it in over 50 years.

However, Acinetobacter baumannii can be effectively killed with the new antibiotic Zosurabalpin, according to researchers from Harvard University and the Swiss healthcare company Hoffmann-La Roche.

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Dr. Kenneth Bradley, one of the researchers and global head of infectious disease discovery with Roche Pharma Research and Early Development, stated that the drug is in its own chemical class and has a unique method of action.

The study’s primary objective was to discover and optimize a molecule capable of penetrating bacterial double membranes and killing them. “These two membranes create a very formidable barrier for entry of molecules like antibiotics,” he said.

“This is a novel approach, both in terms of the compound itself but as well as the mechanism by which it kills bacteria.”

The research found that Zosurabalpin was effective against over 100 CRAB clinical samples. To develop the drug, the scientists researched 45,000 small antibiotic molecules known as tethered macrocyclic peptides to find those that could inhibit bacterial growth. Researchers spent years honing the effectiveness and safety of a select few compounds before settling on a single modified molecule.

By blocking the transport of lipopolysaccharides, which are big molecules essential for maintaining the integrity of the outer membrane and ultimately leading to cell death, Zolofalacpin inhibits the growth of Acinetobacter baumannii.

According to the study, the antibiotic significantly decreased bacterial levels in mice with CRAB-induced pneumonia. Additionally, it prevented the death of mice infected with bacterial sepsis.

“Drug discovery that targets harmful Gram-negative bacteria is a long-standing challenge owing to difficulties in getting molecules to cross the bacterial membranes to reach targets in the cytoplasm. Compounds typically must possess a certain combination of chemical characteristics.”

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Dr. Michael Lobritz, the global head of infectious diseases at Roche Pharma Research and Early Development and an associate participant in the study, stated that the continued absence of effective treatments for antibiotic resistance means that the public health risk of this phenomenon is still a major one on a global scale, regardless of the new finding.

According to CNN, an analysis published in the Lancet in 2022 estimated that antimicrobial resistance was directly responsible for the deaths of about 1.3 million people worldwide in 2019. When put side by side, that year, 860,000 people died from HIV/AIDS and 640,000 from malaria.

The CDC stated in its 2019 Antibiotic Resistance Threats Report that more than 2.8 million cases of infections resistant to antibiotics are reported annually in the United States. Over 35,000 of those individuals lose their lives.

More antibiotics have been developed to treat Gram-positive infections in the last few decades, according to Lobritz. Gram-negative bacteria are more resistant to antibiotics and generally more dangerous. “These  Gram-negative bacteria, they’ve been accumulating resistance to many of our preferred first-line antibiotics for a long time.”

“Innovations are hard to come by. It’s taken us ten years of effort on this project to get it to where it is now, and there’s still more clinical trials to go before it can be determined whether or not it’s a medicine.”

According to the researchers, the method that was used to limit the growth of Acinetobacter, blocking the creation or formation of the outer membrane, could be useful for other difficult-to-treat bacteria such as E. coli. The drug is now in phase 1 clinical trials to assess for safety in humans.