New antibiotic uses novel method to target deadly drug-resistant bacteria, study says

The bacteria, Acinetobacter baumannii, can cause serious infections in the lungs, urinary tract and blood, according to the US Centers for Disease Control and Prevention. It’s resistant to a class of broad-spectrum antibiotics called carbapenems.

Carbapenem-resistant Acinetobacter baumannii, also known as CRAB, was at the top of the World Health Organization’s list of antibiotic-resistant “priority pathogens” in 2017. In the United States, the bacteria caused an estimated 8,500 infections in hospitalized patients and 700 deaths that year, according to the most recent data from the CDC.

CRAB accounts for about 2% of infections found in US hospitals. It’s more common in Asia and the Middle East and causes up to 20% of infections in intensive care units worldwide.

The bacteria thrives in medical environments like hospitals and nursing homes. People at the highest risk of infections are those who have a catheter, who are on a ventilator or who have open wounds from surgery.

The pathogen is so difficult to eliminate that the US Food and Drug Administration has not approved a new class of antibiotic to treat it in more than 50 years, the researchers note in their study, published Wednesday in the journal Nature.

But the researchers, from Harvard University and the Swiss health care company Hoffmann-La Roche, say the new antibiotic, Zosurabalpin, can effectively kill Acinetobacter baumannii.

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

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

Acinetobacter baumannii is a Gram-negative bacteria, meaning it is protected by inner and outer membranes, making it difficult to treat. The goal of the research was to identify and fine-tune a molecule that could cross the double membranes and kill the bacteria.

“These two membranes create a very formidable barrier for entry of molecules like antibiotics,” Bradley said.

The researchers began developing zosurabalpin by examining about 45,000 small antibiotic molecules called tethered macrocyclic peptides and identifying those that could inhibit the growth of different types of bacteria. After years of improving the potency and safety of a smaller number of compounds, the researchers landed on one modified molecule.

Zosurabalpin inhibits the growth of Acinetobacter baumannii by preventing the movement of large molecules called lipopolysaccharides to the outer membrane, where they’re needed to maintain the membrane’s integrity, leading to cell death.

Zosurabalpin was effective against more than 100 CRAB clinical samples that were tested, according to the research.

The antibiotic considerably reduced the levels of bacteria in mice with CRAB-induced pneumonia, the researchers say. It also prevented the death of mice with sepsis brought on by the bacteria.

“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,” the researchers wrote. “Successful compounds typically must possess a certain combination of chemical characteristics.”

Zosurabalpin is in now in phase 1 clinical trials to assess the safety, tolerability and pharmacology of the molecule in humans, according to the study authors.

Despite the new development, the public health threat of antimicrobial resistance remains a huge one globally due to a lack of effective treatments, says Dr. Michael Lobritz, the global head of infectious diseases at Roche Pharma Research and Early Development, who also took part in the research.

Antimicrobial resistance happens when germs like bacteria and fungi evolve enough that they are able to survive encounters with the drugs designed to kill them.

About 1.3 million people worldwide died directly from antimicrobial resistance in 2019, according to a 2022 analysis published in the Lancet. By comparison, HIV/AIDS and malaria caused 860,000 and 640,000 deaths, respectively, that year.

In the US, there are more than 2.8 million antimicrobial-resistant infections each year. More than 35,000 people die as a result, according to the CDC’s 2019 Antibiotic Resistance Threats Report.

In recent decades, more antibiotics have been developed to treat Gram-positive infections, which are typically less harmful and less resistant to antibiotics than Gram-negative bacteria, Lobritz said.

“For these Gram-negative bacteria, they’ve been accumulating resistance to many of our preferred first-line antibiotics for a long time,” he said, and zosurabalpin is a single antibiotic up against a “very formidable” pathogen.

The researchers say the approach used to inhibit the growth of Acinetobacter could help with other hard-to-treat bacteria like E. coli.

“It works by blocking the creation or formation of this outer membrane,” Bradley said, adding that this process is shared across all Gram-negative bacteria. By understanding the biology behind this process, future researchers can learn how to inhibit growth in other bacteria using different modified molecules, he says.

“Innovations are hard to come by,” Lobritz said. “It’s taken us 10 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.”

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